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    • 专利摘要:
    Formula (I): compounds of A- (B) or salts thereof, wherein A = RT 1 -, and R is the drug radical and T 1 = (CO) t or (X) t', and where X = O, S, NR 1C , R 1C is alkyl having carbon atoms from 1 to 5 or H , Or free atoms, t and t 'are t = 1 when t' = 0; t'= 1 day and t = 0 when the constant condition, and zero or one of the, when B = -T B -X 2 at t = 0 when T B = (CO), t' = 0 T B = X, X as defined above; The monovalent radical X 2 is the precursor of A and the precursor of B, respectively, corresponding to the pharmacological action described herein.
    公开号:KR20020005671A
    申请号:KR1020017012971
    申请日:2000-04-11
    公开日:2002-01-17
    发明作者:델솔다토피에로
    申请人:니콕스 에스. 에이.；
    IPC主号:
    专利说明:

    Pharmaceutical compounds
    [1] The present invention relates to novel drugs for systemic and non-systemic use, and compositions thereof, for use in cases of oxidative stress and / or endothelial dysfunction.
    [2] Oxidative stress refers to the generation of free radicals or radicals that cause damage to both cells and cells of surrounding tissue (pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998. p48-54). .
    [3] By endothelial dysfunction refers to a dysfunction associated with vasculature endothelial cells. Vascular endothelial injury is known as one of the important events that can lead to a series of pathological processes affecting several organs and body organs described later (pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998 p1025).
    [4] As is known, oxidative stress and / or endothelial dysfunction is involved in various pathologies as described later. Oxidative stress can also be caused by the toxicity of a wide variety of drugs that seriously affect drug efficacy.
    [5] These pathological events are chronic, debilitating, and very typical for older people. As already described, the drugs used show a markedly worse efficacy in these pathological conditions.
    [6] Examples of pathological conditions caused by oxidative stress and / or endothelial dysfunction or present in older people are:
    [7] Cardiovascular system: Myocardial and vascular ischemia, hypertension, cerebral hemorrhage, arteriosclerosis, etc.
    [8] -Connective tissue: rheumatoid arthritis and related inflammation
    [9] -Lung system: asthma and related inflammation
    [10] -Gastrointestinal: Ulcerative and nonulcerative dyspepsia, enteritis
    [11] Central nervous system: dementia, etc.
    [12] -Urogenital system: erectile dysfunction, incontinence
    [13] -Skin system: eczema, neurodermatitis, acne
    [14] Common infectious diseases (schwarz-KB, Brady "Oxidative stress during viral infection: A review" Free radical Biol. Med. 21/5, 641-649 1996).
    [15] Aging processes can also be considered as actual pathological conditions (see pathophysiology: the biological basis for disease in adults and children, pp. 71-77).
    [16] When known drugs are introduced into pathological patients involved in oxidative stress and / or endothelial dysfunction, they become low activity and / or high toxicity.
    [17] This occurs, for example, in drugs such as anti-inflammatory drugs, cardiovascular drugs, respiratory tract drugs, central nervous contracts, fracture contracts, antibiotics, drugs of the genitourinary system, and endocrine drugs.
    [18] Drug research is moving towards finding new molecules with improved treatment index (efficacy / toxicity ratio) or low hazard / benefit ratios under the above-mentioned pathologies, and treatment indexes for many drugs show low results. In fact, under the conditions of oxidative stress and / or endothelial dysfunction mentioned above, many drugs become low activity and / or high toxicity.
    [19] For example, anti-inflammatory drugs such as NSAIDs, anti-colitis drugs such as 5-aminosalicylic acid and derivatives thereof exhibit the following drawbacks. NSAIDs are particularly toxic when the organism is weakened or affected by conditions of the disease associated with oxidative stress. These conditions are, for example, the following conditions: chronic debilitating diseases affecting age, existing ulcers, existing gastric bleeding, especially cardiovascular, kidney, blood substrate, etc. ("Misoprostol reduces serious gastrointestinal comlications in patients with rtheumatoid arthritis receiving non-steroidal anti-inflammatory drugs.A randomized, double blind, placebo-controlled trial. "FE Silverstein et Al., Ann. Intern. Med. 123/4, 241-9, 1995; Martindale 31a ed. 1996, P 73 , Current Medical Diagnosis and Treatment 1998, P 431 and 794).
    [20] Administration of anti-inflammatory drugs to patients with the above-mentioned pathologies can be done only at a lower dose than that used for the treatment to prevent significant toxicity. Thus, anti-inflammatory activity is low. Beta-blockers used to treat angina, hypertension and cardiac arrhythmia cause side effects on the respiratory organs (breath dysfunction, bronchial contraction), and therefore these drugs may cause pathologies for the organs (asthma, bronchitis). May cause problems for patients with). Thus, beta-blockers can worsen respiratory diseases such as asthma. Therefore, reduced dosages of the agents should be used so that asthma patients no longer harm respiratory function. Therefore, the efficacy of beta-blockers is greatly reduced.
    [21] For example, antithrombotics such as dipyridamole and aspirin used for the prevention of thrombosis have the same drawbacks. In patients with disease associated with oxidative stress and / or endothelial dysfunction, the therapeutic or tolerability of these components, as in the case of aspirin, is greatly reduced.
    [22] For example, bronchodilators such as salbutamol are used to treat asthma and bronchitis, and are used in diseases such as cholinergic incontinence active in the cholinergic system. Administration of these drugs can cause side effects in the cardiovascular system that cause problems for patients with both cardiac and hypertension. Cardiac and hypertension are diseases related to oxidative stress and / or endothelial dysfunction as described above. In addition, these drugs exhibit the same drawbacks as described above.
    [23] The expectorant and mucolytic drugs used to treat the inflammatory state of the respiratory tracts are observed as defects in patients suffering from the conditions described above. Administration of these drugs can cause heartburn and irritability, especially in older people.
    [24] Bone resorption inhibitors, such as diphosphonates (eg alendronate, etc.) are drugs in which high gastrointestinal toxicity is observed. Thus, these drugs can be observed the same defects as those mentioned above.
    [25] Phosphodiesterase inhibitors such as, for example, sildenafil, zaprinast, which are used in cardiovascular and respiratory diseases, are preferred for the pathological conditions of oxidative stress and / or endothelial dysfunction mentioned. Characterized by the same problems with efficacy.
    [26] For example, the antiallergic drugs of cetirizine, montelukast, and the like have been observed with the same problems, especially in the mentioned pathologies related to efficacy.
    [27] For example, ACE inhibitors such as enalapril, captopril and anti-angiotensin drugs such as receptor inhibitors such as losartan are used for cardiovascular treatment. Drawbacks of these drugs can induce side effects (eg cough) in the respiratory tract of the above mentioned pathologies.
    [28] For example, antidiabetic drugs of both insulin-sensitive and hypoglycemic types, such as sulfonylureas, tolbutamide, glypiride, glyclazide, glyburide, nicotinamide, and the like, have no effect on the prevention of diabetic complications. Administration of such drugs can cause side effects such as, for example, gastric lesions. These phenomena are further facilitated by the pathologies mentioned above.
    [29] For example, antibiotics such as ampicillin, clarithromycin, and antiviral drugs such as acyclovir present problems that are considered their content, for example, such drugs cause gastrointestinal sensitization.
    [30] For example, antitumor drugs such as doxorubicin, daunorubicin, cispratinium, and the like have high toxicity to other organs of the stomach and intestines. The toxicity is exacerbated by the above mentioned pathologies of oxidative stress and / or endothelial dysfunction.
    [31] For example, anti-dementants of nicotine and cholinomimetics are characterized by a particularly low content in the pathologies mentioned above.
    [32] Drugs with a steroid structure used to treat acute (asthma, etc.) or chronic diseases (intestinal disease, liver disease, respiratory disease, female genital disease, skin disease, etc.) are particularly effective in various organs under the oxidative stress conditions mentioned above. Characterized by significant toxic effects that cause harm. Hydrocortisone, cortisone, prednisone, prednisolone, fludrocortisone, desoxycorticosterone, methylprednisolone, triamcinolone, paramethasone, betamethasone, dexamethasone, triamcinolone acetonide, fluorinolone acetonide, beclomethasone, Groups of steroid drugs, such as acetosipregnelone, have significant farmaco-toxic effects in various organs, which is why both clinical use and discontinuation are part of a series of very fatal side effects. (See Goodman & Gilman, "The pharmaceutical Basis of Therapeutics" 9th edition, pages 1459-1465, 1996).
    [33] The toxic effects may be referred to as the result of inducing bone tissue to metabolic metabolism and high osteoporosis incidence, to cause hypertension, affect the cardiovascular system, to cause gastrointestinal damage and to damage the gastrointestinal tract ( See Martindale "The extrapharmacopoeia", 30th edition, pages 712-723, 1993).
    [34] Groups of steroid drugs belonging to the bile acids are used for the treatment of hepatic dysfunction and biliary colic. Ursodesuccinic acid is also used for some liver failures (such as cirrhosis of the gall bladder). Their goodness worsens the presence of gastrointestinal complications (chronic liver injury, ulcers, enteritis, etc.). In addition, in the case of bile acids, oxidative stress significantly affects the efficacy of the drug, so that both the efficacy and the tolerability of kenodeoxycholic acid and ursodesuccinic acid are significantly reduced. In particular, it is observed that unwanted effects are enhanced on the liver. Among the steroid compounds, estrogen may be mentioned for the treatment of dislipidaemias, hormonal dysfunction, and feminine organ tumor treatment may also be mentioned. The steroid also exhibits the side effects mentioned above, particularly in the liver.
    [35] According to the prior art mentioned above, it is almost impossible to prevent side effects from treatment (see Goodman's "The pharmaceutical Basis of Therapeutics" 9th edition, page 1474, mentioned above).
    [36] Demonstrating that both patients with oxidative stress and / or endothelial dysfunction have been given improved treatment efficacy, ie low toxicity and / or high efficacy, so that drugs can be administered without exhibiting the drawbacks of prior art drugs. There has been a need for useful drugs.
    [37] It is surprisingly surprising that the mentioned problems presented by the administration of drugs to patients with oxidative stress and / or endothelial dysfunction, or to the elderly in general, are solved by a new class of drugs as described later. .
    [38] The object of the present invention is the following general formula I,
    [39]
    [40] As compounds or salts thereof,
    [41] here:
    [42]
    [43] R is a drug radical
    [44] T 1 = (CO) t or (X) t', where X = O, S, and NR 1C, R 1C is a linear or branched alkyl, or a free valence or H having carbon atoms from 1 to 5, t And t ′ is t = 1 when t ′ = 0; integers and 0 or 1 under the condition t = 0 when t´ = 1,
    [45]
    [46] T B = (CO) when t = 0, T B = X when t ′ = 0, X as defined above;
    [47] Monovalent radical X 2 is such that the corresponding precursor of B conforms to test 5 and / or test 4; Chemical formula Wherein said precursor of T B free atom is saturated with -OZ or Z, Z = H or R 1a , R 1a C 1 -C 10 = linear or possibly branched alkyl, preferably C 1 -C 5 ,
    [48] or Saturation of, where t, t 'is related to the values, depending on whether T B = CO or X, Z I and Z II are the same or different and have Z values;
    [49] With OZ (where Z = H or R 1a ) when the free atom is t´ = 0, or Saturated with XZ (where x and z are as defined above) when t = 0 Is the same as matching at least one of the tests 1-3;
    [50] Trial 1 is an in vivo test performed on four groups of rats of controls (two groups) and treatments (two groups), where one of the controls and one of the treatment groups are each N- 25 mg / kg sc of N-ethylmaleimide (NEM) was administered in a single dose, the control group was treated with a carrier and the treatment groups were carrier + free atoms saturated as described above. The highest dose that can be administered to an animal that is treated with the drug and that is equivalent to the maximum dose that is tolerated by rats that have not received NEM, that is, no obvious toxicity, that is, no symptoms that can be observed symptomatically. Tests administered in high doses: Drugs follow Test 1, ie when groups of rats treated with NEM + carrier + drug show gastrointestinal damage, or groups treated with carrier, carrier + in NEM + carrier + drug treated group. When gastrointestinal damages are observed that are greater than those of the drug treated group or the carrier + NEM treated drug, the drug can be used to formulate compounds of Formulas (I) and (II);
    [51] Test 2 (CIP) is an in vitro experiment in which human endothelial cells in the umbilical vein are collected under standard conditions, then one is treated with a maximum of 10 −4 M concentration of drug in the medium and the other with a carrier. Divided into two groups (each group repeated five times); Then a test in which cumene hydroperoxide (CIP) having a concentration of 5 mM in the medium is added to each of the two groups; The drug conforms to test 2, i.e., if the drug does not have a statistically significant inhibition of CIP-induced apoptosis (cytotoxicity) to p <0.01 for the carrier and the group treated with CIP, then the formula (I) And (II) can be used to prepare compounds;
    [52] Trial 3 (L-NAME) was performed by feeding drinking water for four weeks to four groups of rats (each group consisting of 10 rats) of control groups (two groups) and treatment groups (two groups). In vivo testing, in which one of the control and treatment groups each contained 400 mg / L N-ω-nitro-L-arginine-methyl ester L-NAME) was added to the drinking water for 4 weeks, the control group was administered for 4 weeks, the treatment group was treated with carrier + drug for 4 weeks, the carrier or drug + carrier once daily, The drug can be administered to animals with up to a single dose that is tolerated by a group of mice not pretreated with L-NAME, i.e., no obvious toxicity, i.e. no toxicity that can be observed symptomatically. In high doses; After 4 weeks the drinking water supply was stopped for 24 hours and then sacrificed, blood pressure was measured 1 hour before sacrifice, plasma glutamate pyruvate transaminases (GPT) were measured after sacrifice of rats, and gastric muscle testing To test; The drug meets test 3, ie, in the group of rats treated with L-NAME + carrier + drug as compared to the group treated with carrier alone, the group treated with carrier + drug or the group treated with carrier + L-NAME, respectively. When large liver damages (measured by higher values of GPT) and / or gastric and / or cardiovascular damages (measured by higher blood pressures) are found, the drug is expressed in formulas (I) and (II). Can be used to prepare compounds of;
    [53] Test 4 is an analytical measurement performed by adding a portion of methanol solutions of B or B 1 precursor to a methanol solution of DPPH (2, 2-dipheny1-1-picryl-hydrazyl-free radicals) at a concentration of 10 −4 M; The solution was left at room temperature without light for 30 minutes, and then the absorbance at 517 nm wavelength of the test solution and a solution containing only the same amount of DPPH as the test solution was read; The rate of inhibition induced by the precursors for radical production by DPPH is then
    [54] (1-A S / A C ) × 100
    [55] Calculated as a percentage by
    [56] Wherein A S and A C are absorbance values of a solution containing only the test compound + DPPH and a solution containing only DPPH, respectively;
    [57] If the% inhibition defined above is at least 50%, test 4 is consistent with the compounds used as B precursors;
    [58] Test 5 aliquots 10 -4 M methanol solutions of B precursors into a solution formed by mixing a 100 mM phosphate buffer and a 1 mM Fe II (NH 4 ) 2 (SO 4 ) 2 salt with 2 mM deoxyribose solution in water. Is an analytical measurement carried out by addition); The solution was allowed to stand at a constant temperature of 37 ° C. for one hour, then added to the aliquots of 2.8% acetic acid trichloride and 0.5 M thiobarbituric acid aqueous suspension in order, heated at 100 ° C. for 15 minutes and then the test solution Absorbance is read at 532 nm; The rate of inhibition induced by B precursors against the generation of radicals by Fe II is given by
    [59] (1-A S / A C ) × 100
    [60] Calculated as a percentage through:
    [61] Where A S and A C are the absorbance values of the test compound and the solution containing the iron salt and the solution containing only the iron salt, respectively; Compounds meet test 5 when the% inhibition of the B precursor as defined above is greater than 50%.
    [62] Preferably, the B precursor compound that meets test 5,
    [63] Amino Acids: Asphatic Acid (PI), Histidine (PII), 5-hydroxytryptophan (PIII), 4-thiazolidinecarboxylic acid (PIV), 2-oxo-4-thiazoridinecarboxylic acid (PV )
    [64]
    [65]
    [66] Mono and polyalcohols or thiols: 2-thiouracil (QI), 2-mercaptoethanol (QII), esperidin (QIII), cecaliferol (QIV), 1-α-OHvitamin D2 (QV) From fluorocalcitriol (QVI), 22-oxalcicitrool (QVII), vitamin D3 derivatives (QVIII) esterified with vitamin A, from formula (QIX) compounds, 1α, 25-dihydroxyvitamin D2 (QXI) Derived 24,28-methylene-1α-hydroxyvitamin D2 (QX) Compound, 2-Mercapdoimidazole (QXII)
    [67]
    [68]
    [69]
    [70]
    [71]
    [72]
    [73]
    [74]
    [75]
    [76] Succinic Acid (RI)
    [77]
    [78] Wherein the same or different n ° 3 is an integer such as 0 or 1; The same or different n3 is an integer from 0 to 3; The same or different W is selected from HX, COOH, R ', OR' having X as defined above, where R 'is a carbon atom from 1 to 20 (preferably from 1 to 6 carbon atoms) Linear or possibly branched alkyl with; Rf, ORf, the same as R ', but including Rf containing at least one halogen atom, preferably F, instead of H; At least one of the W radicals is XH when the drug reactor is carboxyl; Or COOH when the reactor is XH;
    [79] If n3 is different from 0 when n ° 3 = 0, the free atoms of the n3 group are saturated with one of R ', OR', Rf, ORf, and H; when n ° 3 = 0 and n3 = 0, the free atoms are H Is saturated.
    [80] Preferably, the B precursor compound that meets test 4 is selected from the class of compounds:
    [81] L-Carnosine (CI), Anserine (CII), Serenocysteine (CIII), Serenomethionine (CIV), Penicylamine (CV), N-acetyl-penicylamine (CVI), Cysteine (CVII ), N-acetyl-cysteine (CVIII), glutathione (CIX) or esters thereof, preferably amino acids selected from ethyl or isopropyl esters:
    [82]
    [83] For compounds (CV), (CVI), (CVII) and (CVIII) in which the SH group is present, the corresponding compound SN (O) s with s of 1 or 2 may also be used in place of SH;
    [84] Hydroxy acids: gallic acid (DI), ferulic acid (DII), gentisic acid (DIII), citric acid (DIV), caffeic acid (DV), hydrocaic acid (DVI), p-coumaric acid (DVII), bar It is selected from nitric acid (DVIII), chlorogenic acid (DIX), kynurene acid (DX), and silingic acid (DXI).
    [85]
    [86]
    [87]
    [88]
    [89] Nordihydroguaiaretic acid (EI), quercetin (EII), catechin (EIII), camphorol (EIV), sulfur etin (EV), ascorbic acid (EVI), isoascorbic acid (EVII), hydroquinone (EVIII), Gosifol (EIX), reduced acid (EX), methoxyhydroquinone (EXI), hydroxyhydroquinone (EXII), propyl gallate (EXIII), sucrose (EXIV), vitamin E (EXV), vitamin A (EXVI), 8-quinolol (EXVII), 3-tert-butyl-4-hydroxyanisole (EXVIII), 3-hydroxyflavone (EXIX), 3,5-tet-butyl-p-hydride Oxytoluene (EXX), p-tetr-butyl-phenol (EXXI), timolol (EXXII), xylbornol (EXXIII), 3,5-di-tetyr-butyl-4-hydroxybenzyl-thioglyco Rate (EXXIV), 4′-hydroxybutylanilide (EXXV), Earcall (EXXVI), Tocol (EXXVII), Isoeugenol (EXXVIII), Eugenol (EXXIV), Piperonyl Alcohol (EXXX), Allo Aromatic and selected from furinol (EXXXI), coniferyl alcohol (EXXXII), 4-hydroxyphenethyl alcohol (EXXXIII), p-coumarin alcohol (EXXXIV), curcumin (EXXXV) Heterocyclic Mono- and Polyalcohols:
    [90]
    [91]
    [92] Aromatic and heterocyclic amines selected from N, N'-diphenyl-p-phenylenediamine (MI), ethoxyquine (MII), thionine (MIII), hydroxyurea (MIV):
    [93]
    [94] 3,3′-thiodipropionic acid (NI), fumaric acid (NII), dihydroxymaleic acid (NIII), thioctic acid (NIV), edetic acid (NV), bilirubin (NVI), 3,4-methylenedioxane Compounds selected from Namsan (NVII), Pyreronylic Acid (NVIII) and comprising at least one free acid group:
    [95]
    [96] Drugs and B precursor compounds are prepared according to known methods of the prior art and for example as described in "The Merck Index, 12a Ed (1996)", incorporated by reference.
    [97] Vitamin D3 derivatives with retinoic acid (QVII) are described in JP 93039261 (see C.A 119 117617); Formula (QVII) compounds are described in EP 562497; 24,28-methylene-1α-hydroxyvitamin D2 (QX) is prepared according to EP 578494; Derivatives of dihydroxyvitamin D2 (QVII) are prepared according to EP 549318.
    [98] Preferred B compounds are those that satisfy test 4.
    [99] The tests carried out to identify the drug precursor of the R radical of formula (I) are specifically:
    [100] Test 1 (NEM): Assessment of gastrointestinal damage from oxidative stress induced by free radicals formed following administration of N-ethylmaleimide (NEM) (HG Utley, F. Bernheim, P. Hochstein "Effects of sulphydrill reagents on peroxidation in microsomes "Archiv. Biochem. Biophys. 118, 29-32 1967).
    [101] The animals (rats) are divided into the following groups (10 animals in one group):
    [102] A) Controls:
    [103] 1 ° group: Treatment: Carrier only (when the drug is administered by mouth, or when the physiological solution is administered parenterally, subcutaneously, intraperitoneally, intravenously or intramuscularly), 1% w / aqueous suspension of carboxymethylcellulose single dose of v: 5 ml / kg),
    [104] Group 2 °: Treatment: carrier as defined above + NEM,
    [105] B) Groups treated with drugs:
    [106] Group I: Treatment: Carrier + Drug,
    [107] Group II: treatment: carrier + drug + NEM,
    [108] Routes of administration are known routes for drugs and can be oral, subcutaneous, intraperitoneal, intravenous or intramuscular.
    [109] The NEM dose is 25 mg / kg in physiological solution (subcutaneous route) and the drug is the one dose corresponding to the maximum dose after one hour or the highest dose that can be tolerated in groups of mice not pretreated with NEM. The highest dose that can be clearly recognized as a symptom of toxicity is administered to the carriers in suspension in the above groups which are not present in animals. Animals are sacrificed after 24 hours and assessment of damage to the mucosal layers of the gastrointestinal tract proceeds.
    [110] The drug is consistent with Test 1, ie damage to the gastrointestinal tract was observed in a group of rats treated with NEM + carrier + drug, or damage to the gastrointestinal tract observed in the group was treated with carrier alone, or treated with carrier + drug. When greater than the damages observed in the group, or in the group treated with carrier + NEM, it can be used to formulate compounds of formulas (I) and (II), and the treatment efficacy of the drug analyzed using special reagents It is not significantly reduced.
    [111] Test 2 (CIP): Endothelial defense parameter against oxidative stress induced by silica men hydroperoxide (CIP).
    [112] Endothelial cells of human umbilical vessels are prepared by normal regular treatment. Fresh navel vessels are soaked in 0.1% collagenase solution and incubated at 37 ° C. for 5 minutes.
    [113] The vessels are then perfused with medium M 199 (GIBCO, Grand Island, NY), pH 7.4, to which other substances are added, as described in the examples. Cells are collected from the perfusate by centrifugation, incubated in a culture flask T-75 and pretreated with human dermalonectin. The cells are then cultured in the same medium with 10 ng / ml bovine hypothalamic growth factor added. When the cells of the initial cell culture (ie, obtained directly from ex-vivo) form a monolayer of fusion cells (8,000,000 cells per flask), the culture is stopped and the layers are washed and trypsinized. Suspensions of cells are transferred to wells of a cell culture plate with 24 wells, half of which are added with the same culture medium containing a drug at a concentration of 10 −4 M and a thermostatic constant temperature of 37 ° C. Is taken from. The cells resulting from the first secondary culture are used for experiments with silica with hydrosulfite (CIP). Cells are identified as endothelial cells by morphological testing and specific immune responses to factors, and the culture is not observed contamination from myocytes or fibroblasts.
    [114] Before starting the test, the cell culture medium is removed and the cell layers are carefully washed with 37 ° C. physiological solution. The wells of the culture plate are then incubated for one hour at 5 mM CIP in the culture medium. The evaluation of cell damage (apoptosis) is carried out by measuring percent variability of DNA disruption relative to the control group (treated with CIP only) and fluorescence fluctuations at wavelengths of 405 to 450 nm.
    [115] The drug is matched to the test, i.e. when significant inhibition of CIP-induced apoptosis (cell damage) with respect to the group treated with CIP alone is not statistically obtained at p <0.01, the formulas (I) and (II) It can be used to prepare the compounds.
    [116] Test 3 (L-NAME): Assessment of endothelial dysfunction induced by administration of L-NAME ((N W -nitro-L-arginine-methylester) J. Clin. Investigation 90, 278-281, 1992) .
    [117] Endothelial dysfunction is assessed by measuring damage to the mucosal layer of the gastrointestinal tract, liver damage induced by administration of L-NAME, and hypertension.
    [118] Animals (rats) are divided into the following groups. The group receiving L-NAME was treated with the compound dissolved at 400 mg / L concentration in drinking water for 4 weeks. The following groups consist of (10 animals in one group):
    [119] A) Controls:
    [120] 1 ° group: carrier only (when the drug is administered by mouth, parenterally, when a physiological solution is administered, a single dose of 1% w / v of an aqueous suspension of carboxymethylcellulose: 5 ml / kg),
    [121] 2 ° group: carrier + L-NAME,
    [122] B) Groups in which the drug was administered:
    [123] Group 3 °: carrier + drug,
    [124] 4 ° group: carrier + drug + L-NAME,
    [125] Routes of administration are known routes for drugs and can be oral, subcutaneous, intraperitoneal, intravenous or intramuscular. The drug is administered at the highest dose that can be tolerated in a group of mice not pretreated with L-NAME, ie at the highest dose that can be seen without any apparent toxicity that can be recognized as a symptom of toxicity in animals. Administered. The drug is administered once every four weeks.
    [126] Animals are sacrificed 24 hours after access to water at the end of 4 weeks of treatment.
    [127] Blood pressure is measured 1 hour before sacrifice, and blood pressure increase is treated as an assessment of damage to vasculature. Damage to the mucosal layer of the gastrointestinal tract is assessed as described in Table 1 (see Example F1). Liver damage is judged by evaluation of glutathione-pyruvic transaminase (GPT) increase after sacrifice.
    [128] The drug meets test 3, ie
    [129] High liver damage (GPT) compared to damage in the group treated with carrier only, or the group treated with carrier + drug, or the group treated with carrier + L-NAME in the group of rats treated with L-NAME + Drug + Carrier and When high gastric and / or high cardiovascular (blood pressure) damage is found, it can be used to prepare compounds of general formulas (I) and (II), and the treatment efficacy of the analyzed drug using special reagents. Is not significantly reduced.
    [130] In the state indicated in the in vivo tests (1 and 3) described above, the treatment index of the drug is reduced because the general dosages for which the drug can be effective are no longer content.
    [131] Test 4 is a colorimetric test to confirm whether the precursor of B inhibits the product of radicals from DPPH (2,2-diphenyl-1-picryl-hydrazyl) (MS Nenster et Al., Atheroscaler. Thromb. 15, 1338-1344, 1995). A 100 mu M solution of methanol of the materials tested was prepared and 0.1 M DPPH solution of methanol was added to each aliquot of the solutions. After shading the solution for 30 minutes at room temperature, the absorbance of the solution was observed at a wavelength of 517 nm simultaneously with the absorbance of the corresponding DPPH solution at the same concentration. The absorbance decreasing with respect to the absorbance of the DPPH solution in the same concentration of test solution is measured. The efficacy of the compounds tested when inhibiting the formation of radicals by DPPH is represented by the formula:
    [132] (1-A S / A C ) × 100
    [133] Where A S and A C are the absorption rates of the solution including the test compound and the solution containing only DPPH, respectively, together with DPPH.
    [134] When the percentage inhibition of radical product from DPPH expressed as percentage rate by the above relationship is greater than 50%, the compound precursor of B is in conformity with test 4.
    [135] Test 5 showed that a 0.1 ml aliquot of 10 -4 M methanolic solutions of the tested products was 0.2 ml of 2 mM deoxyribose, 0.4 ml of 100 mM pH phosphate buffer and 1 mM in 2 mM HCl. A colorimetric test is added to test tubes containing a solution formed by 0.1 ml of. The tubes are then kept at 37 ° C. for one hour. Thereafter, 0.5 ml of 2.8% trichloroacetic acid solution and 0.5 ml of 0.1 M aqueous solution of diobarbituric acid are added to each test tube in order. The reference blank was formed by addition to a test tube containing only 0.1 ml of methanol reactant solution described above. The test tubes are sealed and heated in an oil bath at 100 ° C. for about 15 minutes. Pink coloration improves the size of color in proportion to the amount of deoxyribose that becomes radically oxidative. The solutions are cooled at room temperature and their absorbances at 532 nm are read for the blank. Inhibition induced by the precursor of B for the radical product by Fe II is
    [136] (1-A S / A C ) × 100
    [137] Where A S and A C are the absorption rates of the tested compound + solution containing iron salt and the solution containing iron salt, respectively, wherein the compound is at least 50% inhibition of the radical product defined from the precursor of B above. When test 5 is met.
    [138] Under oxidative stress conditions, the products of formula (I) of the present invention have an improved treatment index compared to the precursor drug.
    [139] For purposes of illustration, the tests mentioned above refer to the following compounds. Let's look at the tables.
    [140] Test 1: precursor drug: indomethacin
    [141] Maximum dose that can be administered to rats: 7.5 mg / kg p.o. Administration at high doses is characterized by intestinal disease, tremor and sedation until toxicity and death (within 24 hours).
    [142] Groups of mice treated with NEM + indomethacin at the doses mentioned above show gastric mucosal damage.
    [143] Indomethacin in the group treated with NEM results in gastric mucosal damage and therefore meets test 1. Indomethacin is therefore used as a drug for preparing compounds (I) and (II) of the present invention.
    [144] Test 2: Prodrugs: Indomethacin, Paracetamol and Mesalamine
    [145] Indomethacin and paracetamol meet Test 2 because the inhibition of apoptosis induced by CIP is not significantly different for the inhibition of apoptosis of the regulators.
    [146] Therefore, the above drugs can be used as drugs for preparing the compounds (I) and (II) of the present invention.
    [147] In contrast, mesalamine does not meet test 2 because mesalamine inhibits apoptosis induced by CIP. Therefore, mesalamine according to test 2 cannot be used as a precursor for preparing compounds (I) and (II) of the present invention. However, the mesalamine submitted to test 1 is found to cause damage to the gastric mucosa.
    [148] Therefore, mesalamine can also be used as a precursor for preparing compounds (I) and (II) of the present invention. Test 3 (L-NAME) precursors: paracetamol, simvastatin, omeprazoil
    [149] Paracetamol and simvastatin meet Test 3 because they cause greater gastric and hepatic damage than those induced by L-NAME + carrier and drug + carrier.
    [150] Therefore, they can be used as precursors for preparing compounds (I) and (II) of the present invention.
    [151] Conversely, we found that omeprazoil does not cause stomach or liver damage, nor does it affect blood pressure. Omphrazoil cannot be used as a precursor to prepare compounds (I) and (II) of the present invention under test 3.
    [152] Test 4 (Test for Compound Precursor of B)
    [153] N-acetylcysteine in this test inhibits the product of radicals induced by DPPH to 100%. Since the percentage rate is above the 50% limit, the drug cannot be used in the present invention as a precursor of B.
    [154] 4-thiazoyridine-carboxylic acid does not inhibit the production of radicals induced by DPPH (Table V) at all. Thus, the drug does not meet the test 4 required by the present invention and can be used as a precursor of B if it meets the test 5.
    [155] Test 5 (Test for Compound Precursor of B)
    [156] Table III relating to this test shows that 4-thiazoyridinecarboxylic acid meets test 5 because the inhibition is 100%. Thus the compound can be used as a precursor of B.
    [157] Preferably in the compounds of formula (I) of the invention, B is XZ and And one or more selected free reactors, wherein X, Z, Z I and Z II are as defined above or COOH, = NH.
    [158] B is of formula (III) having free atoms saturated with a reactor
    [159]
    [160] React with the free compounds of B to react with
    [161] Wherein n 'is an integer between 0 and 3, preferably 1;
    [162] The same or different R TⅨ, TⅨ R 'is H or a linear or branched C 1 -C 4 alkyl, preferably R TⅨ, TⅨ R' is H;
    [163] Y 3 is a saturated, unsaturated or aromatic heterocycle containing at least one nitrogen atom, the ring having 5 or 6 atoms. Y 3 ring may optionally have substituents of, for example, CH 2 OH.
    [164] Y 3 in formula (III) is preferably
    [165]
    [166] Is selected.
    [167] The most preferred compound of Y 3 is Y12 (pyridyl).
    [168] Compound salts of formula (I) may be obtained by reaction with the same molecular weight of the corresponding organic or inorganic acid in an organic solvent such as acetonitrile, tetrahydrofuran.
    [169] Examples of organic acids are hydroxyl, tartaric acid, maleic acid, succinic acid, citric acid.
    [170] Examples of inorganic acids are nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid.
    [171] Derivatives according to the present invention can be used in therapeutic-indications of prodrugs that can benefit from several groups of these drugs illustrated below:
    [172] Anti-Inflammatory NSAIDs: The results of the compounds of the present invention are very good and effective even if the tissues are weak, and are found even under conditions of oxidative stress. The drugs can also be used in these pathologies where inflammation acts as a significant pathogen and is not limited to cancer, asthma, myocardial infarction, and the like.
    [173] adrenergic blockers of the α or β blocker type: the spectrum of action of the compounds of formula (I) has a broader result than that of the starting drugs, and the inhibition of neuronal beta-adrenergic signals, which govern the contraction of blood vessels, has a direct effect on muscle tissue Get involved. Side effects that affect the respiratory tract (shortness of breath, bronchial contraction) are reduced.
    [174] Antithrombotic drugs: Antiplatelet action is enhanced and gastric contents are improved in the case of aspirin derivatives.
    [175] -Bronchodilators and drugs that act on the cholinergic system: Side effects on the cardiovascular organs (retinopathy, hypertension) are reduced.
    [176] Expectorants and mucolytic drugs: improve the goodness of the gastrointestinal tract.
    [177] Diphosphonates: Significantly reduced toxicity associated with the gastrointestinal tract.
    [178] Phosphodiesterase (PDE) inhibitors (bronchodilators): Compounds of the invention can be used to improve treatment efficacy even at the same dose, to administer at lower doses of the drug and to reduce side effects.
    [179] Anti-leukocyte drug: good efficacy.
    [180] ACE inhibitors: good treatment efficacy and low side effects on the respiratory tract (difficulty breathing, coughing).
    [181] Antidiabetic drugs (insulin-sensitive and hypoglycemic), antibiotics, antiviral drugs, antitumor drugs, anticolonitis drugs, dementia drugs: good efficacy and / or content.
    [182] Drugs that can be used as precursors in the general formula of the compounds of the present invention are drugs that meet at least one of the above tests (1, 2, 3). Examples of precursor drugs that can be used are:
    [183] In anti-inflammatory / painkillers, the following may be mentioned by way of example:
    [184] Anti-inflammatory agents: aceclofenac, acemethacin, acetylsalicylic acid, 5-aminoacetylsalicylic acid, alclofenac, aminopropene, amphenac, bendazac, vermopropene, α-bisabolol, bromfenac, bromosalgenin , Butoxoxane, butybufen, carpropene, synmethacin, clidanac, clopirac, diclofenac sodium, diflunisal, ditazoyl, enphenamic acid, etodorax, etofen ammonium, felbinac, fenbufen, pen Clomic Acid, Fendosal, Phenopropene, Pentiazac, Pepradinol, Flufenamic Acid, Flunicin, Fluoxaprofen, Flubiprofen, Glucametacin, Glycylic Acid Glycerate, Ibuprofen, Ibuprosam, India Methacin, indopropene, isofezolac, isoxepac, isoxycam, ketoprofen, ketorolac, rolloxycam, loxoprofen, meclofenamic acid, mefenamic acid salt, melooxycam, mesal Min, methiazine acid, mofezolac, naproxen, niflumum, olsarazine, oxaceprole, jade Prozin, Oxyfenbutazone, Parsalmid, Perisal Salicylic Acid, Phenylsalicylate, Pyrazoilac, Pyroxycam, Pirpropene, Pyranopropene, Proticinic Acid, Salacetamide, Salicylate, O- Acetic acid, salicylic acid, salicylic acid, surindoc, suprofen, succinic zone, tenoxycam, thiapropene acid, tiaramide, tinolidine, tolphenamic acid, tolmetin, tropecin, xenbucin, ximopro Pens, zaltoprofen, jomepilac, civil ciprolol;
    [185] Analgesics: acetaminophen, acetaminosarol, aminochlortenoxazine, 2-amino-4-picolin acetylsalicylic acid, acetylsalicylicsalicylic acid, aniridine, benoxapropene, benzylmorphine, acetate 5-brosalicylic acid, Busetine, buprenorphine, buttorpanol, capsaicin, cinnafen, siramadol, chromatacin, croniccin, codeine, desormorphine, dezosin, dihydrocodeine, dihydromorphine, dimeptanol, dipy Rosetyl, Eptazosin, Etaxazen, Ethyl Morphine, Eugenol, Plutaphenin, Phosphosal, Glafenin, Hydrocodone, Hydromorphone, Hydroxyfetidine, Ibufenac, p-lactophenetide, Levorpanol, meptazinol, metazosin, methopone, morphine, nalbuphine, nicomorphine, norreborganol, normorphine, oxycodone, oxymorphone, pentazosin, phenazorcin, phenolcol, phenoferidine, phenylbuta John, Phenylsalicylic Acid, Phenylamidol, Salicycin, Salicylate Silamide, thiorphan, tramatol, diserine, acrotite;
    [186] For respiratory and urogenital drugs (drugs that act on the cholinergic system and bronchodilators, expectorants / mucolytic drugs, anti-asthma / antiallergic antihistamines), the following may be mentioned:
    [187] Drugs and bronchodilators acting on the cholinergic system: acefilin, albuterol, bambuterol, bamifilin, bebornium methylsulfonic acid, bitolterol, carbuterol, clenbuterol, chlorprenerin, dioxetine Drin, Diphylline, Ephedrine, Epinephrine, Eproginol, Etapredinin, Ethylnorpinephrine, Etophylline, Phenoterol, Plutoprimium, Hexoprelinin, Bromide Pratropium, Isoetarin, Isoprotenerol, Mabuterol, metaprothenerol, oxybutynin, oxytropinum bromide, pybuterol, procaterol, protochillol, proxiphylline, leproterol, limitrol, salmeterol, soterenol, terbutalin , 1-Theobromineacetic acid, thiotropium bromide, tretoquinol, tulobuterol, japrinast, cyclodrin, NS-21, 2-hydroxy-2,2-diphenyl-N- (1,2,3 , 6-tetrahydro-pyridin-4-ylmethyl) acetamide;
    [188] Expectorants / mucolytic drugs: ambrooxol, brominehexine, domiodol, erdossteine, guaiacol, guapenesine, glycerol iodide, letosteine, mesna, sorbenol, stepronin, terpine , Thiopronin;
    [189] Anti-asthmatic / antiallergic antihistamines: acribastine, allocamide, amlexoxox, cetirizine, clobenzepam, chromoglylic acid, clomoline, epinastine, fexofenadine, formoterol, histamine, hydroxyzin , Levocarbastine, rodoxamide, babuterol, metrons, montelukast, nedocromyl, repirinast, ceratodast, supulastastyl acid, terpenadine, tiaramide, urushiol, Brohexine;
    [190] ACE inhibitors: arachepril, benazepril, captopril, sernaphril, silazapril, delapril, enalapril, enalapril, posinopril, imidapril, risinopril, nosartan, mo Beltifril, naphthopidil, perindopril, quinapril, ramipril, spirapril, temocapryl, tradolapril, urapidil;
    [191] Beta-blockers: acebutorol, alprenolol, amosulolol, arotinolol, atenolol, betaxolol, bevantolol, bukmorol, bufetolol, bupralol, bunitrolol, bupranolol, bubutolol Topyrrole, Carrazorol, Capterool, Carvedilol, Celiprolol, Cetamolol, Direvalol, Epanolol, Esmolol, Indenolol, Labetalol, Mepindorol, Metipranolol, Metoprolol, Morphrolol, nadorol, nadoxoroll, nebivorol, nifenarol, nifridarol, oxprenolol, fenbutolol, pindorol, practorol, pronetrol, propranolol, sotarol, sul Pinarol, tallolinol, tetatorol, tilisorol, timolol, toliprolol, xibenolol;
    [192] Antithrombotic drugs and vasodilators: Acetpan, acetylsalicylic acid, argatroban, methane, benprodil, hemisuccinic acid, beziodarone, betahistin, brovincarmine, bufeniod, citcholine, chlorine Benprol, Clopidogrel, Cyclendelic Acid, Dalteparin, Dipyridamol, Droprenylamine, Enoxaparin, Pendylin, Ifenprodil, Iloprost, Indobufen, Isvogrerel, Isosuphrine, Heparin, Ramipivan , Mididorin, nadroparin, nicotinyl alcohol, niliderin, ozagrel, perhexylline, phenylpropanolamine, prenylamine, papavenoline, sodium levparin chloride, lidogrel, sulfoctidyl, tinophedrine , Tinzaparin, triflusal, xanthinolinic acid;
    [193] Diabetic agents: acarbose, carbutamide, glyborgnuglybutiazoyl, miglitol, repaglinide, troglitazone, 1-butyl-3-methanyl-uea, tolesatt, nicotinamide;
    [194] Antitumor drugs: Ancitabine, Anthramycin, Azacytidine, Azaserine, 6-Azauridine, Bicalutamide, Carrubicin, Carboxinophylline, Chlorambucil, Chlorozotocin, Cytarabine, Daunorubicin, Dephosphopamide, demecolsin, denophtherine, 6-diazo-oxo-L-norleucine, docetaxel, doxyfluidine, doxorubicin, droloxifene, etatrexane, eplonitine, enositabine, epi Rubicin, epithiostanol, etanidajoil, etoposide, penretinide, fludarabine, fluorouracil, gemcitabine, hexestrol, idarubicin, ronidamin, mannomustine, melphalan, meno Garyl, 6-mercaptopurine, methotrexane, mitobronitol, mitolactol, mitomycin, mitoxantrone, furdamol, mycophenolic acid, ninophtherine, nogalamycin, paclitaxel, pentostatin, pyrarubicin Sin, pyritrexim, plicamycin, grape phytic acid, sodium former, porphy Mycin, propagermanium, puromycin, lanimuscitin, retinoic acid, loquinimex, streptonigrin, streptozosin, teniposide, tenuazoic acid, thiamiprine, thioguanine, tomusdex, topotecan , Trimetrex acid, tubercidine, ubenimex, vinblastine, vincristine, vindesine, vinorelbine, zorubicin;
    [195] Anti-ulcer drugs: ε-acetamide caproic acid, arbaprostill, setaxic acid, cimetidine, ecabet, enprosteel, esaprazoil, irsogladine, misoprostol, omeprazoil, ornoprostill , Pantophrazoyl, flaunotol, lioprostil, rosaprostol, lordaxic acid, sofalcone, trimoprostill;
    [196] Antihyperlipidemic drugs: atorvastatin, cilastatin, termostatin, flvastatin, lovastatin, mevastatin, nystatin, pentostatin, pepstatin, sodium prevastatin, simvastatin;
    [197] Antibiotics: Amdinocillin, Amoxicillin, Ampicillin, Apalcillin, Apicycline, Aspoxicillin, Azidamphenicol, Azidocillin, Azrocillin, Aztreonam, Benzoylpas, Benzylpenicillin, Viapenem, Bikozamycin, Capreomycin, Carbenicillin, Carindacillin, Kalumonam, Sephacror, Sephadroxil, Sephamandol, Sephatrizin, Sephazedon, Sephazolin, Sepbuferrazone, Cephclidine, Cef Dinir, ceftitorene, cefepime, cefetameth, seppicsim, pefmenoxime, ceftamezoyl, cefminox, cedidimide, cenisid, cefeperazone, celanide, cefotaxime, cetetan, ceftiam , Cytoxitine, cytozofran, cefepimizole, ceftyramide, ceftirom, ceftrozil, ceproxadine, ceftsulodine, ceftazidime, cefteram, ceftezoyl, ceftibuten, ceftiofur , Safety class, ceftriaxone, cepuroxime, cepuzo , Cephacetyl sodium, cephalexin, cephaloclycin, cephaloridine, cephalosporin C, cephalotin, cephapyrine sodium, cepradine, chloramphenicol, chlortetracycline, synoxacin, clavulanic acid , Clometocillin, Clooxacillin, Cyclacillin, Cycloserine, Demeclocycline, Diclooxacillin, Epicillin, Penvecillin, Flomoxef, Flooxacillin, Hetacillin, Imiphenem, Nenampicillin, Laura Capvef, Rimesiclin, Mafenide, Meclocycline, Meropenem, Metaampicillin, Metacycline, Sodium Methicillin, Mezlocillin, Minosicline, Moxalactam, Mupyrosine, Mycin, Nexamycin , Novobiocin, Oxacillin, Panichenem, Potassium Chloride Penicillin G, Penicillin N, Penicillin O, Penicillin V, Potassium Chloride Penicillin, Pipacycline, Piperacillin, Pyrimycin, Porphyromycin, Propicillin, Quinacillin , Riptpenem, lolitetracillin, shaanxi Clin, cedemycin, spectinomycin, sulfactam, sulfenicillin, temocillin, tetraxillin, tacarcillin, tigemonam, tubercidine, azithromycin, clarithromycin, dirithromycin, Enbiomycin, erythromycin, probemycin, middecamycin, myokamycin, oleandomycin, rifabutin, lipamide, rifamycin, lipamycin, locamycin, spiramycin, troleandromycin, biomycin, Virginiamycin; Amikacin, apramycin, arbecasin, dibecasin, dihydrostreptomycin, fortimycin, gentamicin, micronomycin, neomycin, netylmycin, paromomycin, ribostamycin, sisomicin, spec Tinomycin, streptomycin, tobramycin, tropectomycin; Bacampicillin, Cochsylcepchafen, Proxetylcepofoxime, Pannimem, Pibampicillin, Fibcephalexin, Sulamicillin, Talampicillin; Carbomycin, Clindamycin, Lincomycin, Micamycin, Rosaramimycin, Ciprofloxacin, Crinafloxacin, Difloxacin, Enoxacin, Enlofloscin, Floxacin, Flumequine, Glepafloxacin, Lomefloxacin , Nadifloxacin, nalidic acid, norfloxacin, oploxacin, pajufloxacin, pefloxacin, pipemide, pyromidic acid, lufloxacin, sparfloxacin, tosufloxacin, trobafloxacin , Chlomocycline, Guamecycline, Oxytetracycline, Nipurininol, Nipurrazine; p-aminosalicylic acid, p-aminosalicylic acid hydrazide, clofazimin, deoxydihydrostreptomycin, ethambutol, glyconiazide, isoniazid, opiniazide, phenylaminosalicylic acid, rifampin, pipefatin, salinazide, 4-4 ′ Sulfinyldianiline, acediasulfone, dapsone, succisulfone, p-sulfanilibenzylamine, thiazoylsulfone, acetylsulfamethoxypyrazine, maphenide, 4 '-(methylsulfamoyl) sulfanylanilide, sala Zosulfadimidine, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, Sulfaclisoidine, Sulfachitin, Sulfadiazine, Sulfadicuramide, Sulfadimethine, Sulfadoxin, Sulfathidol, Sulfaguanidine, Sulfagua Knol, Sulfalen, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfametijoil, Sulfametomidine, Sulfametoxajo, Sulfamethoxypyridazine, Sulfamethylthiazole, Sulfametrol, Sulfamidorizo Dean, Sulfur , Sulfanyl amide, 2-p- sulfanyl GW carbonyl Reno ethanol, N 4 - sulfanyl rilsul isoquinoline amides, isoquinoline rilru Lea, N- sulfanyl-3,4 keusil vanillyl amide, sulfamic Perrin, Pape alcohol or one trillion days, Sulfaprooxylin, sulfapyrazine, sulfapyridine, sulfasomizoyl, sulfazimazin, sulfatiazoyl, sulfatiurea, sulfisomidine, sulfisoxazoyl, 4-sulfanamidosalicylic acid; Negamycin, Carmonan, Clooxyquine, Nitrooxolin, Arginine, Metronidazole;
    [198] Antiviral drugs: acyclovir, amantadine, sipofovir, cytarabine, didanosine, dideoxyadenosine, edoxsudine, famcyclovir, phloxuridine, gancyclovir, idoxuridine, indanavir, ke Toxal, lamivudine, MADU, pennylclovir, grapephylotoxin, ribavirin, rimantadine, saquinavir, sorivudine, stavudine, trifluridine, valacyclovir, vidarabine, xenazoic acid, zalcitabine, zidobudine;
    [199] Aggregate absorption inhibitors: alendronic acid, butedronic acid, etidronic acid, oxide acid, pamideronic acid, risedronic acid;
    [200] Antidementants include amiridine, lazabemid, mopegiline, salvelozoil, oxyracetam, ipidacrine, nebracetam, tacrine, and belnakrine.
    [201] Anti-inflammatory agents: acetylsalicylic acid, 5-aminoacetylsalicylic acid, carpropene, diclofenac sodium, diflunisal, etodorak, flufenamic acid, flunicin, flurbiprofen, ibuprofen, indomethacin, indopropene, keto Propene, Ketorolac, Rolloxycam, Roxopropene, Meclofenamic Acid, Mefenamic Acid, Meloxycam, Mesalamine, Naproxen, Niplum Acid, Olsarazine, Pyrocamcam, Salsalic Acid, Surindak, Water Propene, tenoxycam, thiapropenic acid, tolfenamic acid, tolmetin, zomepilac, civil ciprolol;
    [202] Analgesics: acetaminophen, acetylsalicylicsalicylic acid, benoxapropene, buprenorphine, butorpanol, capsacin, diaserine, dihydrocodeine, ethylmorphine, eugenol, phenylbutazone, meptazinol, Morphine, nalbuphine, phenazosin, thiorphan, tramatol, acrotite;
    [203] Drugs and bronchodilators acting on the cholinergic system: albuterol, carbuterol, clenbuterol, diphylline, etophylline, phenoterol, bromide pratropium, metaproterenol, oxybutynin, pybuterol, Salmeterol, terbutalin, thiopromium bromide, japriast, cyclodrin, NS-21, 2-hydroxy-2,2-diphenyl-N- (1,2,3,6-tetrahydro- Pyridin-4-ylmethyl) acetamide;
    [204] Expectorant / mucolytic drugs: ambroxol, brominehexine, guaiacol, sobreol;
    [205] Anti-asthmatic / antiallergic antihistamines: cetirizine, histamine, levocarbastine, rodoxamide, montelukast, terpenadine, bromine hexine;
    [206] For cardiovascular drugs (ACE inhibitors, beta blockers, antithrombotic drugs and antitumor drugs), the following may be mentioned:
    [207] ACE inhibitors: captopril, enalapril, ricinopril, nosartan, ramipril;
    [208] Beta-blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindorol, propranolol, timolol;
    [209] Antithrombotic drugs and vasodilators: acetylsalicylic acid, acetoban, argatroban, clopidogrel, dalteparin, dipyridalmol, enoxaparin, heparin, iloprost, midoderin, ozagrerel, phenylpropanolamine , Triflusal;
    [210] Diabetic agents: torestat, nicotinamide;
    [211] Anti-tumor drugs: anthracycin, daunorubicin, doxorubicin, epirubicin, fluorouracil, methotrexane, vinblastine;
    [212] Anti-ulcer drugs: cimetidine, omeprazoil, pantophrazoil;
    [213] Antihyperlipidemic drugs: lovastatin, pravastatin sodium, simvastatin;
    [214] Antibiotics: Amoxicillin, Ampicillin, Aztreonam, Viapenem, Carbenicillin, Sephacror, Sephadroxil, Sephamandol, Sephatrizin, Selcytin, Clavulanic Acid, Diclooxacillin, Imipenem, Meclo Cyclin, metacycline, moksalactam, panipenem, sulbactam, azithromycin, erythromycin, probemycin, myokamycin, rifabutin, lipamide, rifamycin, gentamicin, paromomycin, sisomycin , Bacampicillin, Carbomycin, Clindamycin, Ciprofloxacin, Crinafloxacin, Difloxacin, Enlofloscin, Lomefloxacin, Nadifloxacin, Norfloxacin, Pipemedic acid, Apicycline, Chlomocycline , Oxytetracycline, nifurpynol, nipurrazine, isoniazid, rifampin, pipepafentin, dapson, thiazosulfone, sulfametoxazole, sulfamoxosol, metronidazole, arginine;
    [215] Antiviral drugs: acyclovir, famcyclovir, gancyclovir, pencilclovir, ribavirin, vidarabine, zidovudine;
    [216] Aggregate absorption inhibitors: alendronic acid, etidronic acid, pamidronic acid;
    [217] Antidementants: Oxyracetam, tacrine, belnakrine.
    [218] The above mentioned materials, R precursors, are prepared according to methods known in the art. See, eg, "The Merck Index, 12a Ed. (1996)", incorporated herein by reference. In use, related isomers can be used, including optical isomers.
    [219] Tomoxyprolol is obtained according to the method described in EP 12,866.
    [220] The steroid compound of A = R- has the following structural formula, wherein the hydrogens of the CH groups or the two hydrogen substitutions of the CH 2 groups mentioned in the general formula
    [221]
    [222] The following substituents may be present:
    [223] Position 1-2: may be a double bond;
    [224] Position 2-3: may be a substituent below;
    [225]
    [226] 2-position: may be Cl, Br;
    [227] 3-position: CO, -O-CH 2 -CH 2 -Cl, OH;
    [228] 3-4 position: may be a double bond;
    [229] Position 4-5: may be a double bond;
    [230] Position 5-6: may be a double bond;
    [231] Position 5-10: may be a double bond;
    [232] 6-position: may be Cl, F, CH 3 , -CHO;
    [233] 7 position: may be Cl, OH;
    [234] 9 position: may be Cl, F;
    [235] 11-position: may be OH, CO, Cl, CH 3 ;
    [236] 16 position: CH 3 , OH, = CH 2 ;
    [237] 17-position: OH, CH 3 , OCO (O) ua (CH 2 ) va CH 3 , or
    [238]
    [239] May be (ua is an integer from 0 or 1 and va is an integer from 0 to 4);
    [240] Position 16-17: May be the following:
    [241]
    [242] R and R ', which are the same or different from each other, are hydrogen or linear or branched alkyls of 1 to 4 carbon atoms, preferably Can be;
    [243] R "is Where t2 = 1 when t = 0 and t2 = 0 when t = 1, and t and t1, or t2 and t1, when A does not contain -OH groups, cannot be zero at the same time Provided that t, t1 and t2 are 0 or 1 integers equal to or different from each other;
    [244] The divalent crosslinking group (L) And na, n'a, and n''a, which are the same or different from each other, are integers from 0 to 6, preferably 1 to 3, and nb, n'b, n''b and the same or different from each other; n '''b is an integer equal to 0 or 1, wherein the same or different R 4 , R 5 is selected from hydrogen, linear or branched alkyl of 1 to 5, preferably 1 to 3 carbon atoms;
    [245] Is X as defined above, Is the same as Is OH, , Cl, , , SH, or
    [246]
    [247] Is the same and preferably R "= to be.
    [248] Precursor steroids having a hydroxyl group at position 3 and / or position 11 and / or having a hydroxyl or carboxyl function at the terminal position of R ″ in the precursor steroids are preferred.
    [249] Preferred precursor steroids of A that may be mentioned are those listed below, which can be obtained according to processes known in the art.
    [250] Precursors and individual treatments include those described in The Merck Index, ed 12, 1996, incorporated herein by reference. The precursors (according to the Merck name) are as follows and H 2 , H, R, R ', R "have the meanings mentioned in the compounds listed below: budesonide, hydrocortisone, alclomethasone, Alzestone, beclomethasone, betamethasone, chloroprednisone, clobetazoil, clobetason, clocotoron, clopredol, cortisone, corticosterone, diplazacoat, desonide, desocimethasone, desamethason , Diflorasone Diflucotorone, Difluprenate, Fluazacoat, Fluchloronide, Flumethasone, Flunisolide, Fluorinolone Acetonide, Fluorinide, Fluorocortin Butyl, Fluorocorone, Fluorine Rometorone, fluperonone acetate, fluprednide acetate, fluprednisolone, fluandrenolide, formocotal, hacinolone, halobetasol propionate, halomethasone, halopredone acetate, Hydrocotamate, loteprednol etabonate, meridone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate , Prednisolone sodium phosphate, prednisone, prednisolone, prednylidene, limexolone, triamcinolone, triamcinolone acetonide, 21-acetocypregnenolone, cortivazoil, amcinolone, fluticasone propio Nates, marzipredone, tiscorthol, triamcinolone hexaacetonide, ursodesoxycholic acid, chenodesisocholic acid, mitatrienediol, mozzestrol, ethynylestradiol, estradiol, mestranol.
    [251] Compounds of formula (I) are formulated as mentioned later.
    [252] If a reactor of drugs (eg -COOH, -OH) is involved in the covalent linkage of, for example, esters, amides, ethers, the group can be returned by methods known in the art.
    [253] The reactions used to obtain the compounds of formula (I) are, for example, reactions which lead to the formation of bonds of esters, amides, thioesters known to those skilled in the art.
    [254] If there are other functional groups (COOH and / or HX where X is defined above) in the two compounds of the reaction, they are known in the art, for example Th. Must be protected prior to reaction according to W. Greene, "Protective groups in organic synthesis", Harward University Press, 1980.
    [255] XZ and in radical B (X, Z, Z I and Z II are those defined above), or when there is a COOH, = NH group, in the formula (III) saturated with the reactor so that the free atoms are combined with the B secondary reactor It is possible to bind the corresponding radicals to B. Also in this case the reactors are reactors generally used in the prior art.
    [256] The compound obtained is reacted with a precursor of the drug.
    [257] Compounds of interest of the present invention are formulated with corresponding excipients for parenteral, oral and topical use according to known methods of the prior art, together with general excipients ("Remington's Pharmaceutical Sciences 15a Ed").
    [258] In such formulations the baseline amount of active ingredient is the same or lower than the amount used in the corresponding precursor drug.
    [259] Dosages that can be administered per day are those of prodrugs or, in some cases, daily dosages can be found in publications in the art, such as "Physician's Desk reference."
    [260] The following examples are for the purpose of illustrating the invention and are not to be considered as limiting of the invention.
    [261] Example 1
    [262] Chemical formula
    [263]
    [264] Synthesis of (S, S) -N-acetyl-S- (6-methoxy-α-methyl-2-naphthalene acetyl) cysteine having
    [265] The precursor is naproxen (formula (VI)), and the precursor of B is N-acetylcysteine of formula (C ′).
    [266]
    [267] a) Synthesis of (S, S) -N-acetyl-S- (6-methoxy-α-methyl-2-naphthalene acetyl) cysteine
    [268] To a solution of 6-methoxy-α-methyl-2-naphthalene acetic acid (10 g, 43.4 mol) of chloroform (100 mL) and N, N-dimethylformamide (6 mL), 1,1′-carbonyldiimidoyl (7.04 g, 43.4 mol) is added. After 15 minutes, the resulting solution was treated with (S) -N-acetylcysteine (7.08 g, 43.4 mol) and left at room temperature for 12 hours. The reaction mixture is washed with HCl (5%), and subsequently with a salt solution. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure. The resulting residue is purified by chromatography of silica gel eluted with ethyl acetate. 11.66 g of the desired product are obtained in the form of a white solid with a melting point of 122-126 ° C.
    [269] 1 H-NMR (CDCl 3 ): 7.71-7.65 (3H, m), 7.34 (1H, dd), 7.16-7.09 (2H, m), 6.36 (1H, d), 4.67 (1H, m), 4.00 ( 1H, q), 3.90 (3H, s) 3.32 (2H, t), 1.84 (3H, s), 1.59 (3H, d).
    [270] Example 2
    [271] Chemical formula
    [272]
    [273] Synthesis of (S) -N-acetyl-S- {α-methyl {4- (2-methylpropyl) benzene} acetyl} cysteine having
    [274] The precursor is ibuprofen of formula (VII) and the precursor of B is N-acetylcysteine of formula (CVII).
    [275]
    [276] a) Synthesis of (S) -N-acetyl-S- {α-methyl {4- (2-methylpropyl) benzene} acetyl} cysteine
    [277] 1,1'-carbonyldi in a solution of α-methyl {4- (2-methylpropyl) benzene} acetic acid (10 g, 48.48 mol) of chloroform (100 mL) and N, N-dimethylformamide (6 mL) Midazole (7.86 g, 48.48 mol) is added. After 1 hour, the obtained solution was treated with (S) -N-acetylcysteine (7.91 g, 48.47 mol) and left at room temperature for 24 hours. The reaction mixture is washed with HCl (5%) and then with water and later with saline solution. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure. The resulting residue is purified by chromatography of silica gel eluted with ethyl acetate. 13.3 g of the desired product are obtained in the form of an oil.
    [278] 1 H-NMR (CDCl 3 ): 10.17 (1H, s) 7.13 (2H, d) 6.54 (1H, d), 4.76 (1H, m), 3.93 (1H, q), 3.42-3.30 (2H, m) 2.49 (2H, d), 1.85-1.83 (4H, m), 1.55 (3H, d), 0.93 (6H, d).
    [279] Example 3
    [280] Chemical formula
    [281]
    [282] Synthesis of (S) -N-acetyl-S- [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetyl] cysteine having
    [283] The precursor is indomethacin of formula (VII), and the precursor of B is N-acetylcysteine of formula (CVII).
    [284]
    [285] a) Synthesis of (S) -N-acetyl-S- [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetyl] cysteine
    [286] Of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid (10 g, 28.00 mol) of chloroform (100 mL) and N, N-dimethylformamide (2 mL) To the solution, 1,1'-carbonyldiimidoyl (4.53 g, 28.00 mol) is added. After 1 hour, the resulting solution was treated with (S) -N-acetylcysteine (4.56 g, 28.00 mol) and left at room temperature for 24 hours. The reaction mixture is washed with HCl (5%) and then with water and later with saline solution. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure. The resulting residue is purified by chromatography of silica gel eluted with ethyl acetate. 7.79 g of the desired product are obtained in the form of a yellow solid with a melting point of 129 ° C.
    [287] 1 H-NMR (CDCl 3 ): 12.90 (1H, s), 8.21 (1H, d), 7.69-7.64 (4H, m), 7.06 (1H, d), 6.96 (1H, d), 6.73 (1H, dd), 4.33 (1H, m), 4.02 (2H, s), 3.77 (3H, s), 3.33-2.96 (2H, m), 2.22 (3H, s), 1.78 (3H, s).
    [288] Example 4
    [289] Chemical formula
    [290]
    [291] Synthesis of (S) -N-acetyl- [2-fluoro-α-methyl- (1,1′-biphenyl) -4-acetyl] cysteine having
    [292] The precursor is flubiprofen of formula (VII), and the precursor of B is N-acetylcysteine of formula (CVII).
    [293]
    [294] The compound is synthesized by the treatment described in Example 1. The compound looks like an oil and the yield is 70%.
    [295] 1 H-NMR (CDCl 3 ): 8.38 (1H, d), 7.67-7.50 (6H, m), 7.49-7.53 (2H, m), 4.52-4.41 (1H, m), 4.22 (1H, q), 3.50-3.10 (2H, m), 1.92 (3H, s), 1.58 (3H, d).
    [296] Example 5
    [297] Chemical formula
    [298]
    [299] Preparation of trans-3- [4- {α-methyl {4- (2-methylpropyl) benzene} acetyloxy} -3-methoxyphenyl] -2-propenoic acid having
    [300] The precursor is ibuprofen of formula (VII) and the precursor of B is ferulic acid of formula (DII).
    [301]
    [302] a) Synthesis of trans-3- [4- {α-methyl {4- (2-methylpropyl) benzene} acetyloxy} -3-methoxyphenyl] -2-propenoic acid
    [303] To a solution of α-methyl {4- (2-methylpropyl) benzene} acetic acid (5.03 g, 24.4 mol) of chloroform (100 mL) and N, N-dimethylformamide (5 mL), 1,1'-carbo Nyldimidazoyl (4.25 g, 24.8 mol) is added. After 1 hour, the resulting solution is treated with ferulic acid (4.90 g, 25 mol), ethyl sodium (89 mg) is added and then left to stir for 12 hours at room temperature. The reaction mixture is washed with HCl (5%) and then with water and later with saline solution. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure.
    [304] The resulting residue is purified by chromatography on silica gel eluting with ethyl acetate / n-hexane 7/3. 5.1 g of trans-3- [4- {α-methyl {4- (2-methylpropyl) benzene} acetyl} -3-methoxyphenyl] -2-propenoic acid is white with a melting point of 131 to 137 ° C. Obtained as a solid.
    [305] 1 H-NMR (CDCl 3 ): 7.72 (1H, d), 7.32 (2H, dd), 7.26 (1H, m), 7.16-7.07 (4H, m), 6.98 (1H, d), 6.37 (1H, d), 3.99 (1H, q), 3.73 (3H, s), 2.47 (2H, d), 1.88 (1H, m), 1.63 (3H, d), 0.92 (6H, d).
    [306] Example 6
    [307] Chemical formula
    [308]
    [309] Synthesis of trans-3- [4- [2-fluoro-α-methyl- (1,1′-biphenyl) -4-acetyloxy] -3-methoxyphenyl] -2-propenoic acid having
    [310] The precursor is flurbiprofen of formula (VII) and the precursor of B is ferulic acid of formula (DII).
    [311]
    [312] The compound is synthesized by the treatment described in Example 5. Overall process yield is 60%. The compound looks like an amorphous solid.
    [313] 1 H-NMR (CDCl 3 ): 7.75 (1H, d), 7.52 (2H, m), 7.46-7.26 (4H, m) 7.26 (3H, m), 7.05 (2H, m), 7.00 (1H, d ), 6.37 (1H, d), 4.03 (1H, q), 3.77 (3H, s), 1.65 (3H, d).
    [314] Example 7
    [315] Chemical formula
    [316]
    [317] Of N-acetyl-S-[(S) -α- (2-chlorophenyl) -6,7-dihydrodino [3,2-c] pyridine-5 (4H) acetyl] (S) -cysteine Produce.
    [318] The precursor is clopidogrel of formula (XI), and the precursor of B is N-acecysteine of formula (CVII).
    [319]
    [320] The compound is synthesized according to the procedure described in Example 1. Yield 51%.
    [321] Component Analysis:
    [322] Calculated C: 53.03% H: 4.67% N: 6.18% S: 14.16% Cl: 17.82%
    [323] Measured C: 53.00% H: 4.63% N: 6.15% S: 14.10% Cl: 17.87%
    [324] Example 8
    [325] Chemical formula
    [326]
    [327] Preparation of [3-methoxy-4-hydroxyphenyl] -2-trans-propphenol-4-[(2-amino-3,5-dibromophenyl) methylamino] cyclohexanol ester
    [328] The precursor is an amproxol of formula (XII), and the precursor of B is represented by ferulic acid having formula (DII).
    [329]
    [330] a) Synthesis of 4-[(α-tert-butoxycarbonylamino-3,5-dibromophenyl) methylamino] trans cyclohexanol
    [331] To a mixture of dioxane (35 mL) and water (50 mL) 4-[(2-amino-3,5-dibromophenyl) methylamino] cyclohexanol (5 g, 13.22 mol), triethylamine ( 3.31 mL, 23.7 mol) and ditert-butyldicarbonate (3.46 g, 15.86 mol) are added under stirring. After 24 hours, the solution is concentrated in vacuo, 1% HCl solution is added until neutral pH (pH = 7) and the organic phase is extracted with ethyl acetate.
    [332] The resulting solution was treated with ferulic acid (4.90 g, 25 mol), ethyl sodium (89 mg) was added and then left to stir for 12 hours at room temperature. The organic phase is anhydrous with sodium sulfate and evaporated in vacuo. 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl) methylamino] cyclohexanol is obtained without further purification.
    [333] b) (3-methoxy-4-hydroxyphenyl) -2-trans-propphenol-4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl) methylamino] cyclo Synthesis of Hexanol Ester
    [334] To a solution of ferulic acid (4 g, 20.5 mol) in tetrahydrofuran (40 ml) cooled to 0 ° C, 1,1'-carbonyldiimidazol (3.34 g, 20.5 mol) is added. After 10 minutes, the solution was treated with 4-[(2-ter-butoxycarbonylamino-3,5-dibromophenyl) methylamino] cyclohexanol (9.8 g, 20.5 mol) and 4 hours at room temperature. To react. The reaction mixture is concentrated in vacuo, treated with methylene chloride, washed with 1% HCl solution and then with water. The organic phase is anhydrous with sodium sulfate and then evaporated in vacuo. The remaining residue is purified by chromatography on silica gel eluting with n-hexane / ethyl acetate 1/1. (3-methoxy-4-hydrocyphenyl) -2-trans propphenol 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl) methylamino] cyclohexanol ester Obtained.
    [335] c) Synthesis of [(3-methoxy-4-hydrocy) phenyl] -2-trans propphenol-4-[(2-amino-3,5-dibromo-phenyl) methylamino] cyclohexanol ester
    [336] Ethyl acetate (50 mL) of (3-methoxy-4-hydroxyphenyl) -2-trans propphenol-4-[(2-tert-butoxycarbonylamino-) cooled to 0 ° C. and kept under stirring. To a solution of 3,5-dibromo-phenyl) methylamino] cyclohexanol ester (2 g, 3.06 mol), 5N HCl solution of ethyl acetate is added. Finally the precipitate is filtered off. The initial product obtained is treated with ethyl acetate and 5% sodium bicarbonate solution is added. The mixture is mixed and the bicarbonate solution is replaced with water. The mixture is mixed again, the organic phase is recovered, anhydrous with sodium sulfate and evaporated at reduced pressure. [3-methoxy-4-hydroxyphenyl] -2-transpropphenol-4-[(2-amino-3,5-dibromo-phenyl) methylamino] cyclohexanol ester is obtained. Yield 41%.
    [337] Component Analysis:
    [338] Calculated C: 50.90% H: 4.62% N: 4.94% Br: 28.22%
    [339] Measured C: 50.81% H: 4.63% N: 4.89% Br: 28.18%
    [340] Example 9
    [341] Chemical formula
    [342]
    [343] Preparation of S-[[2- [4- (4-chlorophenyl) phenylmethyl) -1-piperazinyl] ethoxy] acetyl] penicillamine
    [344] The precursor is cetirizine of formula (XIV), and the precursor of B is penicillamine (CV).
    [345]
    [346] a) Synthesis of S-[[2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetyl] N-tert-butoxycarbonylphenylsilamine
    [347] The compound is prepared according to the procedure described in Example 1, using N-tert-butoxycarbonylphenylsilamine instead of N-acetyl cysteine.
    [348] b) Synthesis of S-[[2- [4- (4-chlorophenyl) phenylmethyl) -1-piperazinyl] ethoxy] acetyl] penicillamine
    [349] In order to remove the protecting group of N-tert-butoxycarbonyl and restore the function of the amine, the compound is obtained from the previous material by the method described in step C) of Example 8. Yield 29%.
    [350] Component Analysis:
    [351] Calculated C: 58.96% H: 6.59% N: 7.63% S: 5.83% Cl: 16.44%
    [352] Measured C: 58.89% H: 6.50% N: 7.58% S: 5.79% Cl: 16.40%
    [353] Example 10
    [354] Chemical formula
    [355]
    [356] Preparation of N-acetyl-S-[(S) -1- [N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-proline] cysteine having
    [357] The precursor is enamel April of formula (XV) and the precursor of B is N-acetylcysteine (CV).
    [358]
    [359] The compound is synthesized according to the method described in Example 1. Yield 35%.
    [360] Component Analysis:
    [361] Calculated C: 58.30% H: 6.96% N: 7.84% S: 5.98%
    [362] Measured C: 58.25% H: 6.94% N: 7.88% S: 5.87%
    [363] Example 11
    [364] Chemical formula
    [365]
    [366] Of N-nicotinol-β-alanyl (L) -histidine
    [367] The precursor is nicotinamide of formula (XIII), and the precursor of B is carnosine (CII).
    [368]
    [369] a) Synthesis of N-nicotinol-β-alanyl (L) -histidine
    [370] To a solution of nicotinic acid (2.5 g, 20.5 mol) of tetrahydrofuran (40 mL) cooled to 0 ° C., 1,1′-carbonyldiimidazol (3.34 g, 20.5 mol) is added. After 10 minutes, (L) -carnosine (4.6 g. 20.5 mol) is added to the solution and left to stir for 4 hours at room temperature. The reaction mixture is concentrated in vacuo, treated with methylene chloride and washed with 1% HCl followed by water. The organic phase is anhydrous with sodium sulfate and then evaporated in vacuo. The remaining residue is chromatographed with a column of silica gel eluted with ethyl acetate. N-nicotinol-β-alanyl (L) -histidine is recovered. Yield 45%.
    [371] Component Analysis:
    [372] Calculated C: 54.49% H: 4.88% N: 21.27%
    [373] Measured C: 54.30% H: 5.00% N: 21.30%
    [374] Example 12
    [375] Chemical formula
    [376]
    [377] Preparation of 7- [2-hydroxy-3- [3-methoxy-5-hydroxybenzoyl] trans-2-propenol] deophylline having
    [378] The precursor is depilin of formula (XVI) and the precursor of B is ferulic acid (DII).
    [379]
    [380] The drug is synthesized according to the method described in Example 8. Yield 28%.
    [381] Component Analysis:
    [382] Calculated C: 57.66% H: 5.32% N: 10.13%
    [383] Measured C: 57.70% H: 5.37% N: 10.11%
    [384] Example 13
    [385] Chemical formula
    [386]
    [387] Preparation of N-acetyl-S- (2-acetylbenzoyl) cysteine having
    [388] The precursor is acetylsalicylic acid of formula (VII), and the precursor of B is N-acetylcysteine (CVII).
    [389]
    [390] The compound is synthesized according to the procedure described in Example 1. Yield 63%.
    [391] Component Analysis:
    [392] Calculated C: 51.69% H: 4.65% N: 4.31% S: 9.86%
    [393] Measured C: 51.64% H: 4.68% N: 4.33% S: 9.89%
    [394] Example 14
    [395] Chemical formula
    [396]
    [397] 4- [3- [3-methoxy-5-hydroxyphenyl] -2-propenoxy] -2-methyl-N-2-pyridinyl-2H-1,2-benzodiazine-3 Preparation of -Carboxymidamide-1,1-Dioxide
    [398] The precursor is pyoxycamp of formula (i), and the precursor of B is represented by ferulic acid having formula (DII).
    [399]
    [400] The compound is synthesized according to the procedure described in Example 8. Yield 25%.
    [401] Component Analysis:
    [402] Calculated C: 59.14% H: 4.17% N: 8.31% S: 6.31%
    [403] Measured C: 59.01% H: 4.09% N: 8.20% S: 6.21%
    [404] Example 15
    [405] Chemical formula
    [406]
    [407] Of S- [2-[(2,6-dichlorophenyl) amino) benzeneacetyloxy] penicillamine
    [408] The precursor is diclofenac of formula (VII), and the precursor of B is penicillamine (CV).
    [409]
    [410] The compound is synthesized by the treatment described in Example 9. Yield 53%.
    [411] Component Analysis:
    [412] Calculated C: 49.88% H: 3.66% N: 7.30% S: 8.32% Cl: 18.40%
    [413] Measured C: 49.90% H: 3.64% N: 7.29% S: 8.25% Cl: 18.35%
    [414] Example 16
    [415] Starting with flurbiprofen of formula (VIII), the precursor of B is (L) -4-thiazoyridine carboxylic acid of formula (PIV)
    [416]
    [417] Synthesis of 3- [2-Fluoro-α-methyl- (1,1′-biphenyl) -4-acetyl] thiazoyridine-4-carboxylic acid of
    [418]
    [419] a) Synthesis of 3- [2-fluoro-α-methyl- (1,1'-biphenyl) -4-acetyl] thiazoyridine-4-carboxylic acid
    [420] 2-fluoro-α-methyl- (1,1'-biphenyl) -4-acetic acid (10 g, 41 mol) of toluene (100 mL) and N, N-dimethylformamide (10 mL) cooled to 0 ° C. To a solution of), oxalyl chloride (3.52 mL, 82 mol) is added. After 2 hours, the solution is evaporated at reduced pressure at room temperature. The resulting residue was dissolved in acetone (50 mL), and this solution was acetone (50 mL) of 4-thiazoyridinecarboxylic acid (5.44 g, 41 mol) and triethylamine (14.9 mL, 106) cooled to 0 ° C. Mol) solution. After 2 hours the mixture is acidified with 4N HCl and concentrated in vacuo, the residue is treated with ethyl acetate and the organic phase is first washed with 2N HCl and then with water. The organic phase is anhydrous with sodium sulfate and evaporated at reduced pressure. By crystallization with ethyl acetate / n-hexane, 9.4 ml of the desired product is obtained in the form of a white solid with a melting point of 142 to 147 ° C.
    [421] 1 H-NMR (CDCl 3 ): 7.74-7.62 (4H, m), 7.35 (2H, t), 7.18-7.13 (2H, m), 5.06 (1H, m), 4.63 (1H, d), 4.42 ( 1H, d), 4.14 (1H, q), 3.13 (2H, m), 1.53 (3H, d).
    [422] Example 17
    [423] Starting with naproxene of formula (VI)
    [424]
    [425] Synthesis of 3- (6-methoxy-α-methyl-2-naphthaleneacetyl) thiazoyridine-4-carboxylic acid of.
    [426] The precursor of B is (L) -4-thiazoyridine carboxylic acid (Formula IV).
    [427]
    [428] a) Synthesis of 3- (6-methoxy-α-methyl-2-naphthaleneacetyl) thiazoyridine-4-carboxylic acid
    [429] Oxalyl chloride in a solution of 6-methoxy-α-methyl-2-naphthaleneacetic acid (4.02 g, 17.5 mol) of toluene (30 mL) and N, N-dimethylformamide (0.3 mL) cooled to 0 ° C (2.92 mL, 34.06 mol) is added. After 2 hours, the solution is evaporated at reduced pressure at room temperature. The resulting residue was dissolved in acetone (50 mL), and this solution was acetone (50 mL) of 4-thiazoyridinecarboxylic acid (2.33 g, 17.5 mol) and triethylamine (6.34 mL, 45.5) cooled to 0 ° C. Mol) solution. After 2 hours the mixture is acidified with 4N HCl and concentrated in vacuo, the residue is treated with ethyl acetate and the organic phase is first washed with 2N HCl and then with water. The organic phase is anhydrous with sodium sulfate and evaporated at reduced pressure. 4.43 g of the desired product are obtained in the form of a white solid with a melting point of 165 to 168 ° C.
    [430] 1 H-NMR (CDCl 3 ): 7.75-7.66 (3H, m), 7.34 (1H, d), 7.14-7.11 (2H, m), 5.14 (1H, m), 4.80-4.61 (2H, m), 4.07 (1H, q), 3.91 (3H, s), 3.30-3.23 (2H, m), 1.53 (3H, d).
    [431] Example 18
    [432] Starting from naproxen of formula (VI)
    [433]
    [434] Synthesis of 3- (6-methoxy-α-methyl-2-naphthaleneacetyl)-(R) -2-oxothiazolidin-4-carboxylic acid of
    [435] The precursor of B is (L) -2-oxo-4-thiazoyridine carboxylic acid (formula (VV)).
    [436]
    [437] a) Synthesis of 3- (6-methoxy-α-methyl-2-naphthaleneacetyl)-(R) -2-oxothiazolidin-4-carboxylic acid
    [438] Oxalyl chloride in a solution of 6-methoxy-α-methyl-2-naphthaleneacetic acid (7.0 g, 30.4 mol) of toluene (100 mL) and N, N-dimethylformamide (10 mL) cooled to 0 ° C (5.23 mL, 61 mol) is added. After 2 hours, the solution is evaporated at reduced pressure at room temperature. To a solution of the obtained residue dissolved in tetrahydrofuran (50 mL), 2-oxothiazolydine-4-carboxylic acid (4.07 g, 27.6 mol) in tetrahydrofuran (50 mL) cooled to -10 ° C, A mixture consisting of 4-dimethylaminopyridine (0.84 g, 6.9 mol) and triethylamine (7.69 ml, 55.2 mol) is added. It is left at room temperature for 24 hours. The reaction mixture is washed with HCl (5%) and then with water. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure. The resulting residue is purified by chromatography of silica gel eluting with methylene chloride / methanol 95/5. 6.79 g of the desired product are obtained in the form of an amorphous solid.
    [439] Component Analysis:
    [440] Calculated C: 60.16% H: 4.76% N: 3.89% S: 8.92%
    [441] Measured C: 60.22% H: 4.80% N: 3.83% S: 8.91%
    [442] Example 19
    [443]
    [444] Of [2-[(2,6-dichlorophenyl) amino) benzeneacetyloxy]-(L) -histidine
    [445] The prodrug of the compound of the present invention is diclofenac of formula (VII), and the precursor of B is (L) -histidine of formula (PII).
    [446]
    [447] a) Synthesis of [2-[(2,6-dichlorophenyl) amino) benzeneacetyloxy]-(L) -histidine
    [448] To a solution of diclofenac (3 g, 10.13 mol) of tetrahydrofuran (50 mL) cooled to 0 ° C., 1,1′-carbonyldiimidazol (1.69 g, 10.13 mol) is added while stirring. After 10 minutes, the solution is treated with (L) -histidine (1.57 g. 10.13 mol) and left to stir at room temperature for 4 hours. The reaction mixture is concentrated in vacuo, treated with methylene chloride, washed sequentially with 1% HCl and then with water. The organic phase is anhydrous with sodium sulfate and evaporated in vacuo. The remaining residue is purified by chromatography on a column of silica gel eluted with ethyl acetate. [2-[(2,6-dichlorophenyl) amino) benzeneacetyloxy]-(L) -histidine is obtained. Yield 61%.
    [449] Component Analysis:
    [450] Calculated C: 55.45% H: 4.18% N: 12.92% Cl: 16.36%
    [451] Measured C: 55.48% H: 4.23% N: 12.88% Cl: 16.25%
    [452] Pharmacological experiments
    [453] Example
    [454] Acute poisoning
    [455] Acute poisoning was measured by administering a cannula of 20 grams of a mass of each of the compositions to be tested to a group of 10 rats by mouth with 2% w / v of carboxymethylcellulose aqueous suspension. Animals were observed for 14 days. After administration of a single dose of 100 mg / kg, the animals in the group showed no symptoms of intoxication.
    [456] Example F1
    [457] Test 1-Experimental Model with N-ethylmaleimide (NEM) in vivo: A study of gastric tolerability of some drugs selected as precursors of the compositions of the present invention.
    [458] Animals (rats, 200g weight) are divided into the following groups (10 per group).
    [459] A) Controls:
    [460] 1 ° group: Treatment: Carrier only (when the drug is administered by mouth, or when the physiological solution is administered parenterally by subcutaneous, intraperitoneal, intravenous or intramuscular route, 1% of carboxymethylcellulose aqueous suspension 1% w / v Dosage: 5 ml / kg)
    [461] 2 ° group: Treatment: carrier + NEM,
    [462] B) Groups in which each drug was administered:
    [463] Group I: Treatment: Carrier + Drug,
    [464] Group II: Treatment: Carrier + Drug + NEM.
    [465] The drugs contained in this experiment are as follows (Table I): indomethacin, ambroxol, mesalamine, sodic allenronate, tacrine, omeprazoil, misoprostol.
    [466] Indomethacin, ambroxol and alendronate are administered by mouth, mesalamine by the internal colon (rectal) route, and tacrine, omeprazoil, misoprostol by subcutaneous route.
    [467] The maximum tolerated dose determined by administering each substance to animals not treated with NEMs by these routes is reported in Table I. Enteropathy, diarrhea, depression, tremor and sedation were seen in animals by a single dose higher than reported in the table.
    [468] In this experimental model, animals were initially treated with NEM with a subcutaneous injection of a single dose of 25 mg / kg physiological solution. The drug is administered in a carrier suspension after 1 hour. Animals were sacrificed after 24 hours, and damage measurements of the gastrointestinal mucosa were counted in each group of mice with lesions on them by visual examination. The total number of rats is then divided by the total number of rat groups and multiplied by 100. The percentages thus obtained are reported in Table I. The table shows that gastric lesions could not be detected in the rat group treated with the drugs without NEM.
    [469] All rats in group II (NEM treated) showed gastric lesions after administration of the following drugs: indomethacin, ambroxol, mesalamine, sodic allenronate, tacrine. Therefore, the drugs can be used to synthesize the preparations of the present invention.
    [470] Instead omeprazoil, microprostol cannot be used to prepare the products of the present invention based on the results provided in test 1.
    [471] Example F2
    [472] Test 2 (in vitro): Inhibition of apoptosis (DNA disruption) induced in endothelial cells by CIP in the presence of some drugs selected as precursors of the compositions of the present invention.
    [473] Precursor Drugs (Table II): Indomethacin, Paracetamol, Clopidogrel, Salbutamol, Ambroxol, Sodic Allendronate, Diphylline, Kethyrizine, Enaapril, Nicotinamide, Ampicillin, Akiclovir , Mesalamine, tacrine, simvastin, omeprazoil, misoprostol.
    [474] Endothelial cells of the human umbilical vein are prepared according to standard methods. The new umbilical vein is filled with mass 0.1% collagenase solution and incubated at 37 ° C. for 5 minutes.
    [475] The vein was then sprayed onto a medium of M199 (GIBCO, Grand Island, NY) pH 7.4 containing 0.1% collagen (mass / volume), 10% fetal bovine serum (10mcg / ml), heparin sodium (50mcg / Ml), thymidine (2.4mcg / ml), glutamine (230mcg / ml), penicillin (100UI / ml), streptomycin (100mcg / ml) and streptomycin B (0.125mcg / ml) are added. Cells are harvested from perfusate by centrifugation at 800 rpm, collected in a culture flask (T-75), and pretreated with human piburonectin. Cells are then collected in the same medium and bovine hypothalamic growth factor (100 ng / ml) is added. When cells of the original cell culture (cells removed ex vivo of the venous vein) form a monolayer of confluent cells (approximately 8,000,000 cells / flasks), the collection is stopped and the layers are washed and trypsinized. The cell suspension has 24 wells, half of which are transferred to wells of the culture plate to which the same medium containing the drug is added at a concentration of 10 -4 M, with constant humidity (90%), CO 2 at a temperature of 37 ° C. Collected at = 5%. When the drug cannot be dissolved in the medium, it is first dissolved in a small amount of dimethyl sulfoxide. The maximum amount of dimethyl sulfoxide that can be added to the medium is 0.5%. Only cells from this first subculture are used to be tested with cumene hydroperoxide (CIP). Cells are identical to endothelial cells by morphological testing and characteristic immune responses to factor VII; These cultures show no contamination from myocytes or fibroblasts.
    [476] Before starting the test, the cell medium is removed and the cell layers are carefully washed with standard physiological solution neutralized to pH 7.0 with 0.1 M phosphate. Each well component is then incubated for 1 hour with CIP suspension in 5 mM concentration medium. Measurement of cell damage (apoptosis) is performed by determining the percent change in DNA disruption of cultures containing drug + CIP relative to CIP-only controls. The% change in DNA fragmentation is determined by measuring the fluorescence change of the test specimens with respect to the visual density of the controls by a BX60 Olympus Microscope (Olympus Co., Rome) set at a wavelength of 405-450 nm. Fluorescence of each sample is determined in 5 replicates. Statistical measurements were performed with the Student's t test (p, 0.01).
    [477] The results are listed in Table II and indomethacin, paracetamol, clopidogrel, salbutamol, sodickalendronate, diphylline, ketirizine, enarafril, nicotinamide, ampicillin, akiclovir, tacrine, omeprazoil Certainly cell destruction is not inhibited; Therefore these drugs can be used to prepare the formulations of the invention.
    [478] In contrast, ambroxol, mesalamine and simvastatin inhibit cell destruction. Therefore, it cannot be used to prepare the preparations of the present invention based on the results of test 2.
    [479] Example F3
    [480] Test 3-nitro -L- arginine-methyl ester (N W -nitro-L-arginine -methyl ester following L-NAME) experimental model in vivo with N W: some drugs screened as precursors of the compositions of the present invention Gastrointestinal resistance (gastric duct injuries), liver (GPT single dose, glutamic acid pyruvintransaminase) resistance and cardiovascular (blood pressure) resistance of the children.
    [481] The experimental model employed is J. Clin. Investigation 90, 278-281, 1992.
    [482] Endothelial dysfunction is measured by determining the damage induced by L-NAME administration by determining cardiovascular or vascular endothelial damage such as mucosal layers of the gastrointestinal tract, liver damage (increased GPT) and hypertension.
    [483] Animals (rats, average weight 200 g) are divided into the groups described below. The group receiving L-NAME was treated for 4 weeks with the composition dissolved at 400 mg / l concentration in drinking water. It consists of the following groups (10 per group).
    [484] A) Controls:
    [485] 1 ° group: Treatment: Carrier only (Carboxymethylcellulose aqueous suspension 1% w / v, single dose: 5 ml / kg when drug is administered by mouth, physiological solution by parenteral route)
    [486] 2 ° group: Treatment: carrier + L-NAME,
    [487] B) Groups treated with drugs:
    [488] Group I: Treatment: Carrier + Drug,
    [489] Group II: Treatment: Carrier + Drug + L-NAME.
    [490] The drugs used in the trials are paraketamamol, doxorubicin, simvastatin, omeprazoyl and misoprostol. Each drug is administered once a day for four weeks.
    [491] The maximum tolerated single dose of drug administered to animals is determined by measuring the presence of enteropathy, diarrhea, depression, pre- and sedation in animals at each single dose estimated by investigation of untreated animals.
    [492] Access to water is forbidden after four weeks and animals are sacrificed after one hour.
    [493] One hour before sacrifice, blood pressure was measured, indicating an increase in blood pressure.
    [494] Damage to the gastric mucosa is measured as described above in Test 1 (ex. F1). Liver damage is determined by post-sacrifice measurement with glutamic acid pyruvintransaminase (GPT increase).
    [495] The drug conforms to test 3 and can therefore be used to prepare the compositions of the invention. Higher liver damage (higher GPT values) and / or higher gastric damage and / or in the group treated with carrier + drug + L-NAME compared to the group treated with carrier alone or with a carrier plus drug Higher cardiovascular damage (higher blood pressure) is found.
    [496] The test results are recorded in Table IV. % Gastric lesions were determined as in trial 1. % GPT and% blood pressure values refer to the corresponding values found in animals of the first group of controls. The mean value of blood pressure in this group was 105 ± 8 mmHg.
    [497] The results obtained indicate that paraketamamol, doxorubicin, and simvastatin cause liver damage and gastrointestinal disease (GPT values and gastric disease in% compared to both groups treated with drug without L-NAME and controls treated with L-NAME). Is higher).
    [498] Therefore, these drugs can be used to prepare the formulations of the invention.
    [499] Instead omeprazoil and microprostol should not be used to prepare the inventive formulations based on this test.
    [500] Example F4
    [501] Test 4: Inhibition of radical formation from DPPH of some substances used as B precursors.
    [502] This method is based on a colorimeter test in which DPPH (2, 2-dipheny1-1-picryl-hydrazyl) is used as compound forming radicals (MS Nenseter et Al., Atheroscler. Thromb. 15. 1338-1344, 1995). .
    [503] Methanol solutions of the test substance with a final concentration of 100 μM are prepared initially. 0.1 ml of each of these solutions is added to a 1 ml aliquot of DPPH 0.1 M methanol solution and the final volume is 1.5 ml. After 30 minutes of storage at room temperature where light is blocked, the absorbance at wavelength 517 nm is read. The decrease in absorbance relative to the absorbance of a solution containing the same concentration of DPPH is determined. The efficacy of a test compound to inhibit the production of radicals or antiradical activity is expressed by the formula:
    [504] (1-A S / A C ) × 100
    [505] Where A S and A C are the absorbance values of the solution containing + DPPH and the absorbance value of the solution containing only DPPH, respectively, together with the test compound.
    [506] The compounds used according to the invention conform to test 4 if the inhibition of radical production is at least 50% as described above.
    [507] In Table V, the results obtained with the following materials are reported: N-acetylcysteine, cysteine, ferulic acid, (L) -carnosine, gentisic acid, 4-thiazoyridinecarboxylic acid and 2-oxo-4- Thiazolidinecarboxylic acid.
    [508] Table V shows the following:
    [509] N-acetylcysteine, cysteine, ferulic acid, (L) -carnosine, and gentisic acid comply with test 4 because they inhibit at least 50% of the generation of radicals induced by DPPH.
    [510] 4-thiazoyridinecarboxylic acid and 2-oxo-4-thiazoyridinecarboxylic acid are ineffective because they do not inhibit radical production from DPPH. Therefore, if they comply with test 5, they can be used as precursors of sulfide B in the synthesis of the compounds according to the invention.
    [511] Example F5
    [512] Test 5: Inhibition of radical formation from Fe II from compounds used as B precursors.
    [513] 0.1 ml aliquots of 10 -4 M methanolic solutions of 4-thiazoyridinecarboxylic acid and 2-oxo-4-thiazoyridinecarboxylic acid were dissolved in 1 mM Fe II (NH 4 ) 2 (SO 4 ) 2 in 2 mM HCl. 0.1 ml, 0.2 ml of 2 mM deoxyribose and 0.4 ml of 100 mM pH7.4 phosphate buffer are added to the test tubes containing the aqueous solution formed by mixing. These tubes are then left to stand at 37 ° C for one hour. Each test tube is then added with 0.5 ml of 2.8% aqueous trichloroacetic acid solution and 0.5 ml of 0.1M thiobarbituric acid aqueous solution in that order. The reference blanks were made in lieu of 0.1 ml aliquots of the aqueous test compound metaol solution containing 0.1 ml methanol above. The tubes are closed and heated in an oil bath at 100 ° C. for 15 minutes. Pink pigmentation develops at an intensity proportional to the amount of deoxyribose treated by radical oxidative decomposition. The solutions are cooled at room temperature and the absorbances at 532 nm are read for blank.
    [514] The inhibition induced against radical production from Fe II by the precursors of B or B1 or CT C -YH, where the free equilibrium is filled as defined above, is determined in percent through the formula:
    [515] (1-A S / A C ) × 100
    [516] Where A S and A C are the absorbance values of the solution containing the + iron salt together with the test compound and the absorbance values of the solution containing only the iron salt, respectively.
    [517] The results are reported in the attached table, which shows that both acids act to inhibit radical production from iron ions. Therefore these compounds can be used as B precursors to obtain the compounds of the present invention.
    [518] Example F6
    [519] Gastric resistance test of the compounds according to the present invention for the corresponding precursors in the conditions of phytogenic resistance induced by L-NAME (N W -nitro-L-arginine-methyl ester).
    [520] Example F3 is repeated and this measures the gastro tolerance of the following precursor drugs and their derivatives according to the invention:
    [521] Diclofenac and its derivatives according to Ex. 15,
    [522] Pyroxicam and its derivatives according to Ex.
    [523] Aspirin and its derivatives according to Ex.
    [524] The results are recorded in the accompanying Table IV, which shows that by administering the same dose of the compound of the present invention and the corresponding precursor drug, the incidence of gastropathy is significantly reduced or not seen in the groups treated with the compounds of the present invention. Shows no.
    [525] Example 20
    [526] Starting with propranolol of formula (XIV)
    [527]
    [528] 3 (3-methoxy-4-hydroxy-phenyl) -2-trans propenoic acid 1-[(1-methylethyl) amino] -3- (1-naphthaleneoxy) -2-propyl of formula (CCI) Ester synthesis.
    [529] Precursor B is ferulic acid (DII).
    [530]
    [531] Compound (CCI) was obtained following the procedure in Example 8. Yield: 30%.
    [532] Component Analysis
    [533] Calculated: C: 71.71 H: 6.71 N: 3.22
    [534] Measured: C: 71.79 H: 6.75 N: 3.17
    [535] Example 21
    [536] Starting from benfulodilhemisukinate of formula (XXXI)
    [537]
    [538] N-acetyl-S- [1- [5- (2,5-dihydro-5-oxo-3-furanyl) -3-methyl-2-benzofuranyl] ethyloxy-4- of the formula (CCII) Synthesis of oxo-butanoyl] -cysteine.
    [539] The precursor B is N-acetylcysteine (CVIII).
    [540]
    [541] Compound (CCII) was obtained following the procedure in Example 1. Yield: 13%.
    [542] Component Analysis
    [543] Calculated: C: 57.25 H: 5.00 N: 2.78 S: 6.37
    [544] Measured: C: 57.30 H: 5.02 N: 2.72 S: 6.35
    [545] Example 22
    [546] Starting with ferulic acid of formula (DII) and 4-hydroxyomeprazoyl of formula (XXII)
    [547]
    [548] Formula (CCIII) 5-methoxy-2-[[[(3-methoxy-4-hydroxy-phenyl) -2-trans propenoyl] -3,5-dimethyl-2-pyridinyl] methyl] sul Synthesis of Finyl] -1H-benzimidazol.
    [549]
    [550] Compound (CCIII) was obtained following the procedure in Example 8. Yield: 43%.
    [551] Component Analysis
    [552] Calculated: C: 61.65 H: 4.78 N: 8.30 S: 6.33
    [553] Measured: C: 61.71 H: 4.85 N: 8.25 S: 6.35
    [554] Example 23
    [555] Starting with simvastatin of formula (XXI) and ferulic acid of formula (DII)
    [556]
    [557] [1S- [1α, 3α, 7β, 8β, (2S * , 4S * )]]-2,2-dimethylbutanoic acid 1,2,3,7,8,8-hexahydro-3 of formula (CCIV) -, 7-Dimethyl-8- [2- [tetrahydro-4-[(3-methoxy-4-hydroxy-phenyl) -2-trans propenohydroxy] -6-oxo-2H-pyran-2 Synthesis of --yl] ethyl] -1-naphthalenyl ester.
    [558]
    [559] Compound (CCIII) was obtained following the procedure in Example 8. Yield: 21%.
    [560] Component Analysis
    [561] Calculated: C: 70.68 H: 7.80
    [562] Measured: C: 70.70 H: 7.82
    [563] Example 24
    [564] Starting with Ampicillin of Formula (XVI) and Penicillamine of Formula (CV)
    [565]
    [566] Synthesis of S- [4-D-α-aminobenzylphenylaminoyl] phenicylamine of the formula (CCV).
    [567]
    [568] Compound (CCV) was synthesized according to the procedure of Example 9. Yield: 13%.
    [569] Component Analysis
    [570] Calculated: C: 52.48 H: 5.87 N: 11.66 S: 13.34
    [571] Measured: C: 52.51 H: 5.90 N: 11.61 S: 13.30
    [572] Example 25
    [573] Starting with aquiclovir of formula (XVII) and histidine of formula (PII)
    [574]
    [575] Synthesis of 9-[[2-[(S) -α-amino-1H-imidazoyl-4-propanoyl-oxy] ethoxy] -methyl] guanine of Formula (CCVI)
    [576]
    [577] Compound (CCVI) was obtained following the procedure in Example 19. Yield: 17%.
    [578] Component Analysis
    [579] Calculated: C: 50.14 H: 4.77 N: 27.29
    [580] Measured: C: 50.17 H: 4.75 N: 27.22
    [581] Example 26
    [582] Starting from arendronic acid of formula (XXXVI) and ferulic acid of formula (DII)
    [583]
    [584] Synthesis of [4-amino-[(3-methoxy-4-hydroxy-phenyl) -2-trans-propenyl] -1-hydroxybutylidene] biphosphonic acid of formula (CCVII)
    [585]
    [586] Compound (CCVII) was obtained following the procedure in Example 8. Yield: 10%.
    [587] Component Analysis
    [588] Calculated: C: 39.54 H: 4.98 N: 3.29 P: 14.57
    [589] Measured: C: 39.57 H: 5.01 N: 3.24 P: 14.56
    [590] Example 27
    [591] Starting with tacrine of formula (XXXV) and histidine of formula (PII)
    [592]
    [593] Synthesis of 5-[[(S) -α-amino-1H-imidazoyl-4-propanoyl] amino] -1,2,3,4-tetrahydroacridine of Formula (CCVIII)
    [594]
    [595] Compound (CCVIII) was obtained following the procedure in Example 19. Yield: 15%.
    [596] Component Analysis
    [597] Calculated: C: 68.04 H: 6.31 N: 20.88
    [598] Measured: C: 68.08 H: 6.37 N: 20.84
    [599] Example 28
    [600] Starting with doxorubicin of formula (XXXII) and ferulic acid of formula (DII)
    [601]
    [602] (8S-cis) -10-[(3-amino, 2,3,6-tri-deoxy-α-L-lyxo-exopyranosyl) oxy] -7,8,9,10 of formula (CCIX) -Tetrahydro, 6,8,11-trihydroxy-8-[[[(3-methoxy-4-hydroxy-phenyl) -2-trans propenoyl-oxy-] methyl-oxo] -1- Synthesis of Methoxy-5,12-naphthakenedione
    [603]
    [604] Compound (CCIX) was obtained following the procedure in Example 8. Yield: 10%.
    [605] Component Analysis
    [606] Calculated: C: 61.75 H: 5.18 N: 1.95
    [607] Measured: C: 61.81 H: 5.22 N: 1.90
    [608] Example F7
    [609] Example F1 was recorded in three groups of rats (10 in each group), all of whom received an NEM,
    [610] a. Control: Mediator formed with 1% w / v of carboxymethylcellulose aqueous suspension,
    [611] b. One group (group b-comparison) in which ibuprofen 100 mg / kg (0.48 mmole / kg) + N-acetylcysteine 79 mg / kg (0.48 mmole / kg) was simultaneously administered to the mediator,
    [612] c. One group (group c) to which the medium was administered 170 mg / kg (0.48 mmole / kg) of ester between indomethacin and N-acetylcysteine (ref. Ex. 2).
    [613] The results are reported in Table 7 and the mixture administered in group b (comparative) is less effective than the compounds of the invention administered in group c in reducing gastric lesions.
    [614] Test 1: Gastric tolerance (oxidative stress conditions) of representative drugs among the drug classes described herein of animals not treated with NEM or treated. The percent incidence is calculated as the ratio of the number of animals in which gastric lesions were found to the total number of groups. compoundSingle dose (mg / kg) / administration routeGastric- enteropathy (% incidence) No NEMWith NEM Carrier inmetamethamphetamine brush mesalamine alendronate tacrine omeprazoyl microprostol7.5 / p.o.25 / p.o.750 / i.c.15 / p.o.1 / s.c.30 / s.c.0.5 / s.c.00000000010080609010000
    [615] p.o. = blowjob; i.c. = by internal colon pathway; s.c. = by subcutaneous route.
    [616] Test 2: Inhibition of apoptosis (DNA disruption) induced in endothelial cells by CIP in the presence of a representative compound among the drug classes described herein. compound% Apoptosis for controls treated with CIP alone Indomethacinparacetamolclopidogrelsalbutamolambrosolallendronatediphyllineketyrazineenrapril nicotinamide ampicillinacquilovirmesalamintacleansimvastinomeprajoil951201109070160951158098949574907290
    [617] Test 5: Screening for effects in the list of substances that inhibit the production of radicals induced by Fe IIcompound% Radical suppression from Fe IIBlank 2-oxo-4-thiazolidine carboxylic acid thiazolidine carboxylic acid histidine010010090
    [618] Test 3: Gastric tolerance (induced gastrointestinal damage), liver (GPT single dose, glutamic acid pyruvate) of some compounds of the representative components of the drug classes described herein under conditions of endothelial trouble induced by L-NAME Transaminases) tolerance and cardiovascular (blood pressure) resistance. Results associated with blood pressure and GPT are expressed in% values compared to those found in animals treated with carrier only without L-NAME. compoundSingle dose (mg / kg) / injection routeBlood pressure%GPT%Gastroenterology% Carrier Paraketamoltoxorubicin simvastatin omeprazoyl microprostol300 / i.p.1 / i.p.50 / p.o.30 / s.c.0.5 / s.c.No L-NAMEHas L-NAMENo L-NAMEHas L-NAMENo L-NAMEHas L-NAME 1001081208510010015215514514815014210018019512210010015550036022016016002030000309010060105
    [619] Test 4: Screening efficacy of listed compounds in inhibiting radical production from DPPH compound% Inhibition of radical production from DPPH Solvent N-acetylcysteine cysteine ferulic acid (L) -carnoscingentic acid 4-thiazolidincarboxylic acid 2-oxo-4-thiazolidincarboxylic acid histidine01001001008080000
    [620] Gastric Tolerance of Derivatives According to the Present Invention Compared to Gastric Tolerance of Precursor Drugs AidSingle dose (mg / kg)Gastric incidence% carrier 30 Diclofenac Diclofenac Derivatives (Ex. 15) Pyrroxycampyrroxycam Derivatives (Ex. 14)1010101050501001010001000
    [621] Gastric tolerance test following oral administration of NEM (Ex. 7) CountiesSingle dose (mg / kg) p.o.Gastric incidence% Ibustropene ester with control group b-comparison with ibuprofen (A) + N-acetylcysteine (B) group cN-acetylcysteine-100 (A) +79 (B) 170.4-6010
    权利要求:
    Claims (18)
    [1" claim-type="Currently amended] The following compounds of formula (I) or salts thereof
    (Ⅰ)
    here:

    R is a drug radical
    T 1 = (CO) t or (X) t', where X = O, S, and NR 1C, R 1C is a linear or branched alkyl, or a free valence or H having carbon atoms from 1 to 5, t And t ′ is t = 1 when t ′ = 0; integers and 0 or 1 under the condition t = 0 when t´ = 1,

    T B = (CO) when t = 0, T B = X when t ′ = 0, X as defined above;
    Monovalent radical X 2 is such that the corresponding precursor of B conforms to test 5 and / or test 4; Said precursor of formula -T B -X 2 , wherein the T B free atom is saturated with -OZ or Z, Z = H or R 1a , R 1a C 1 -C 10 = linear or possibly branched alkyl, preferably Let's say C 1 -C 5 ,
    or Saturation, where t is associated with t 'values, depending on whether T B = CO or X, Z I and Z II are the same or different and have Z values;
    With OZ (where Z = H or R 1a ) when the free atom is t´ = 0, or Drug A = RT 1 -that is saturated with XZ (where X and Z are as defined above) when t = 0 and is equal to at least one of the tests 1-3;
    Trial 1 is an in vivo test performed on four groups of rats of controls (two groups) and treatments (two groups), where one of the controls and one of the treatment groups are each N- 25 mg / kg sc of N-ethylmaleimide (NEM) was administered in a single dose, the control groups were treated with a carrier and the treatment groups of the formula A = RT 1 − in which the carrier + free atom was saturated as described above. The highest dose that can be administered to an animal with a dose that is equivalent to the maximum tolerated by rats that do not receive the NEM, that is, no obvious toxicity, that is, no symptomatologically observable toxicity. The dose is a test: The drug follows test 1, ie when the group of rats treated with NEM + carrier + drug shows gastrointestinal damage, or in the group treated with NEM + carrier + drug, the carrier + drug Groups treated as or When gastrointestinal damage is observed that is greater than that of the group treated with carrier + NEM, the drug can be used to formulate compounds of formulas (I) and (II);
    Test 2 (CIP) was performed in vitro, in which human endothelial cells in the umbilical vein were collected under standard conditions, then one was treated with a maximum of 10 −4 M concentration of drug in the medium and the other treated with a carrier. Divided into groups (each group repeated five times); Then a test in which cumene hydroperoxide (CIP) having a concentration of 5 mM in the medium is added to each of the two groups; The drug conforms to test 2, i.e., if the drug does not have a statistically significant inhibition of CIP-induced apoptosis (cytotoxicity) to p <0.01 for the carrier and the group treated with CIP, then the formula (I) And (II) can be used to prepare compounds;
    Trial 3 (L-NAME) was performed by feeding drinking water for four weeks to four groups of rats (each group consisting of 10 rats) of control groups (two groups) and treatment groups (two groups). In vivo testing, in which one of the control and treatment groups each contained 400 mg / L N-ω-nitro-L-arginine-methyl ester L-NAME) was added to the drinking water for 4 weeks, the control group was administered for 4 weeks, the treatment group was treated with carrier + drug for 4 weeks, the carrier or drug + carrier once daily, The drug can be administered to animals with up to a single dose that is tolerated by a group of mice not pretreated with L-NAME, i.e., no obvious toxicity, i.e. no toxicity that can be observed symptomatically. In high doses; After 4 weeks the drinking water supply was stopped for 24 hours and then sacrificed, blood pressure was measured 1 hour before sacrifice, plasma glutampyrubintransaminase (GPT) was measured after sacrifice of rats, and gastric muscle testing was performed. Is a test; The drug meets test 3, ie, in the group of rats treated with L-NAME + carrier + drug as compared to the group treated with carrier alone, the group treated with carrier + drug or the group treated with carrier + L-NAME, respectively. When large liver damages (measured by higher GPT) and / or gastric and / or cardiovascular damages (measured by higher blood pressure) are found, the drug is represented by the formulas (I) and (II). Can be used to prepare compounds of;
    Test 4 is an analytical measurement performed by adding a portion of methanol solutions of B or B 1 precursor to a methanol solution of DPPH (2, 2-dipheny1-1-picryl-hydrazyl-free radicals) at a concentration of 10 −4 M; The solution was left at room temperature without light for 30 minutes, and then the absorbance at 517 nm wavelength of the test solution and a solution containing only the same amount of DPPH as the test solution was read; The rate of inhibition induced by the precursors for radical production by DPPH is then
    (1-A S / A C ) × 100
    Calculated as a percentage by
    Wherein A S and A C are absorbance values of a solution containing only the test compound + DPPH and a solution containing only DPPH, respectively;
    If the% inhibition defined above is greater than 50%, test 4 is consistent with the compounds used as B precursors;
    Test 5 aliquots 10 -4 M methanol solutions of B precursors into a solution formed by mixing a 100 mM phosphate buffer and a 1 mM Fe II (NH 4 ) 2 (SO 4 ) 2 salt with 2 mM deoxyribose solution in water. Is an analytical measurement carried out by addition); The solution was left at a temperature of 37 ° C. for one hour, then added sequentially to aliquots of 2.8% acetic acid trichloride and 0.5 M thiobarbituric acid aqueous suspension, heated at 100 ° C. for 15 minutes and then absorbance of the test solutions. Is read at 532 nm; Inhibition rates induced by B precursors against the generation of radicals by Fe II are given by
    (1-A S / A C ) × 100
    Calculated as a percentage through:
    Where A S and A C are the absorbance values of the test compound and the solution containing the iron salt and the solution containing only the iron salt, respectively; Compounds according to Test 5 or salts thereof when the% inhibition of B precursor as defined above is 50% or more.
    [2" claim-type="Currently amended] The compound of claim 1, wherein the B precursor compound meets test 5,
    Amino Acids: Asphatic Acid (PI), Histidine (PII), 5-hydroxytryptophan (PIII), 4-thiazolidinecarboxylic acid (PIV), 2-oxo-4-thiazoridinecarboxylic acid (PV )


    Mono and polyalcohols or thiols: 2-thiouracil (QI), 2-mercaptoethanol (QII), esperidin (QIII), cecaliferol (QIV), 1-α-OHvitamin D2 (QV) From fluorocalcitriol (QVI), 22-oxalcicitrool (QVII), vitamin D3 derivatives (QVIII) esterified with vitamin A, from formula (QIX) compounds, 1α, 25-dihydroxyvitamin D2 (QXI) Derived 24,28-methylene-1α-hydroxyvitamin D2 (QX) Compound






    Succinic Acid (RI)

    Wherein the same or different n ° 3 is an integer such as 0 or 1; The same or different n3 is an integer from 0 to 3; The same or different W is selected from HX, COOH, R ', OR' having X as defined above, where R 'is linear or possibly branched alkyl having carbon atoms from 1 to 20 (preferably Is 1 to 6 carbon atoms); Rf, ORf, the same as R ', but including Rf containing at least one halogen atom, preferably F, instead of H; At least one of the W radicals is XH when the drug reactor is carboxyl; Or COOH when the reactor is XH;
    If n3 is different from 0 when n ° 3 = 0, the free atoms of the n3 group are saturated with one of R ', OR', Rf, ORf, and H; when n ° 3 = 0 and n3 = 0, the free atoms are H Compounds selected from compounds saturated with:
    [3" claim-type="Currently amended] The compound of claim 1, wherein the B precursor compound meets test 4
    L-Carnosine (CI), Anserine (CII), Serenocysteine (CIII), Serenomethionine (CIV), Penicylamine (CV), N-acetyl-penicylamine (CVI), Cysteine (CVII ), N-acetyl-cysteine (CVIII), glutathione (CIX) or esters thereof, preferably amino acids selected from ethyl or isopropyl esters:

    For compounds (CV), (CVI), (CVII) and (CVIII) in which the SH group is present, the corresponding compound SN (O) s with s of 1 or 2 can also be used in place of SH;
    Gallic acid (DI), ferulic acid (DII), genisic acid (DIII), citric acid (DIV), caffeic acid (DV), hydrocaic acid (DVI), p-coumaric acid (DVII), vanylic acid (DVIII) Hydroxy acids selected from chlorogenic acid (DIX), kynurene acid (DX), and silingic acid (DXI):


    Nordihydroguaiaretic acid (EI), quercetin (EII), catechin (EIII), camphorol (EIV), sulfur etin (EV), ascorbic acid (EVI), isoascorbic acid (EVII), hydroquinone (EVIII), Gosifol (EIX), reduced acid (EX), methoxyhydroquinone (EXI), hydroxyhydroquinone (EXII), propyl gallate (EXIII), sucrose (EXIV), vitamin E (EXV), vitamin A (EXVI), 8-quinolol (EXVII), 3-tert-butyl-4-hydroxyanisole (EXVIII), 3-hydroxyflavone (EXIX), 3,5-tet-butyl-p-hydride Oxytoluene (EXX), p-tetr-butyl-phenol (EXXI), timolol (EXXII), xylbornol (EXXIII), 3,5-di-tetyr-butyl-4-hydroxybenzyl-thioglyco Latex (EXXIV), 4′-hydroxybutylenilide (EXXV), wirecall (EXXVI), tocol (EXXVII), isoeugenol (EXXVIII), eugenol (EXXIV), ferreronyl alcohol (EXXX), Aromatic and selected from allopurinol (EXXXI), coniferyl alcohol (EXXXII), 4-hydroxyphenethyl alcohol (EXXXIII), p-coumarin alcohol (EXXXIV), curcumin (EXXXV) Heterocyclic Mono- and Polyalcohols:

    Aromatic and heterocyclic amines selected from N, N'-diphenyl-p-phenylenediamine (MI), ethoxyquine (MII), thionine (MIII), hydroxyurea (MIV):

    3,3′-thiodipropionic acid (NI), fumaric acid (NII), dihydroxymaleic acid (NIII), thioctic acid (NIV), edetic acid (NV), bilirubin (NVI), 3,4-methylenedioxane Compounds selected from Namsan (NVII), Pyreronylic Acid (NVIII) and comprising at least one free acid group:

    Compounds selected from the compound classes of.
    [4" claim-type="Currently amended] 4. Compounds according to claim 2 or 3, wherein the B precursor compounds meet test 4.
    [5" claim-type="Currently amended] 5. The compound of claim 1, wherein B is XZ and At least one free reactor of which X, Z, Z I and Z II are as defined above or COOH, = NH.
    [6" claim-type="Currently amended] The compound of formula (III) according to claim 5, wherein B has free atoms saturated with the reactor
    (III)
    React with the free compounds of B to react with
    Wherein n 'is an integer between 0 and 3, preferably 1;
    The same or different R TⅨ, TⅨ R 'is H or a linear or branched C 1 -C 4 alkyl, preferably R TⅨ, TⅨ R' is H;
    Y 3 is a saturated, unsaturated or aromatic heterocycle containing at least one nitrogen atom, the ring having 5 or 6 atoms.
    [7" claim-type="Currently amended] The compound of claim 6, wherein Y 3 of formula (III) is

    Compounds selected from.
    [8" claim-type="Currently amended] 8. A compound according to claim 7, wherein Y 3 is Y12 (pyridyl).
    [9" claim-type="Currently amended] The method according to any one of claims 1 to 8, wherein the prodrugs of the compounds of formula (I) are
    Anti-inflammatory drugs, analgesics, drugs that act on the cholinergic system and bronchodilators, expectorant-mucus solutions, anti-asthma-antiallergic drugs, antihistamines, ACE inhibitors, beta-blockers, antithrombotic drugs, Compounds selected from vasodilators, diabetic agents, antitumor, antiulcer, antihyperlipidemic, antibiotic, antiviral drugs, aggregate absorption inhibitors, antidementants.
    [10" claim-type="Currently amended] The method of claim 9, wherein the precursor drugs are
    Anti-inflammatory agents: aceclofenac, acemethacin, acetylsalicylic acid, 5-aminoacetylsalicylic acid, alclofenac, aminopropene, ampfenac, bandazac, vermopropene, α-bisabolol, bromfenac, bromosalgenin , Butoxoxane, butybufen, carpropene, synmethacin, clidanac, clopirac, diclofenac sodium, diflunisal, ditazoyl, enphenamic acid, etodorax, etofenam acid, felbinac, fenbufen, fencloze Acids, fensal, phenopropene, penthiazac, pepradinol, flufenamic acid, flunicin, fluoxapropene, flurbiprofen, glucetacin, glycol salicylate, ibuprofen, ibuproxam, indometha Sin, Indoprofen, Isopezolac, Isoxepac, Isoxicam, Ketoprofen, Ketorolac, Rolloxycam, Roxoprofen, Meclofenamic Acid, Mefenamic Acid, Meloxycam, Mesalamine, Methizinic acid, mofezolac, naproxen, niflumsan, olsarazine, oxaceprole, oxaf Gin, oxyphenbutazone, parsalmid, peroxalic acid, phenylacetylsalicylate, pyrazoyllac, pyroxicam, pyrpropene, pyranopropene, proticinic acid, salaceamide, salicylate, O-acetic acid , Salicylic acid, salicylic acid, surindak, suprofen, succinic zone, tenoxycam, thiapropenic acid, tiaramide, tinolidine, tolphenamic acid, tolmetin, tropecin, xenbucin, ximoprofen , Zaltoprofen, jomepilac, civil ciprolol;
    Analgesics: acetaminophen, acetaminosarol, aminochlortenoxazine, 2-amino-4-picolin acetylsalicylic acid, acetylsalicylicsalicylic acid, aniridine, benoxapropene, benzylmorphine, acetate 5-brosalicylic acid, Busetine, buprenorphine, buttorpanol, capsaicin, cinnafen, siramadol, chromatacin, croniccin, codeine, desormorphine, dezosin, dihydrocodeine, dihydromorphine, dimeptanol, dipy Rosetyl, Eptazosin, Etaxazen, Ethyl Morphine, Eugenol, Plutaphenin, Phosphosal, Glafenin, Hydrocodone, Hydromorphone, Hydroxyfetidine, Ibufenac, p-lactophenetide, Levorpanol, meptazinol, metazosin, methopone, morphine, nalbuphine, nicomorphine, norreborganol, normorphine, oxycodone, oxymorphone, pentazosin, phenazorcin, phenolcol, phenoferidine, phenylbuta John, Phenylsalicylic Acid, Phenylamidol, Salicycin, Salicylate Amides, tea climb board, Tra matol, diacerein, other discrete arc;
    Drugs and bronchodilators acting on the cholinergic system: acefilin, albuterol, bambuterol, bamifilin, bebornium methylsulfonic acid, bitolterol, carbuterol, clenbuterol, chlorprenerin, dioxetine Drin, Diphylline, Ephedrine, Epinephrine, Eproginol, Etapredinin, Ethylnorpinephrine, Etophylline, Phenoterol, Plutoprimium, Hexoprelinin, Bromide Pratropium, Isoetarin, Isoprotenerol, Mabuterol, metaprothenerol, oxybutynin, oxytropinum bromide, pybuterol, procaterol, protochillol, proxiphylline, leproterol, limitrol, salmeterol, soterenol, terbutalin , 1-Theobromineacetic acid, thiotropium bromide, tretoquinol, tulobuterol, japrinast, cyclodrin, NS-21, 2-hydroxy-2,2-diphenyl-N- (1,2,3 , 6-tetrahydro-pyridin-4-ylmethyl) acetamide;
    Expectorants / mucolytic drugs: ambrooxol, brominehexine, domiodol, erdossteine, guaiacol, guapenesine, glycerol iodide, letosteine, mesna, sorbenol, stepronin, terpine , Thiopronin;
    Anti-asthmatic / antiallergic antihistamines: acribastine, allocamide, amlexoxox, cetirizine, clobenzepam, chromoglylic acid, clomoline, epinastine, fexofenadine, formoterol, histamine, hydroxyzin , Levocarbastine, rodoxamide, babuterol, metrons, montelukast, nedocromyl, repirinast, ceratodast, supulastastyl acid, terpenadine, tiaramide, urushiol, Brohexine;
    ACE inhibitors: arachepril, benazepril, captopril, sernaphril, silazapril, delapril, enalapril, enalapril, posinopril, imidapril, risinopril, nosartan, mo Beltifril, naphthopidil, perindopril, quinapril, ramipril, spirapril, temocapryl, tradolapril, urapidil;
    Beta-blockers: acebutorol, alprenolol, amosulolol, arotinolol, atenolol, betaxolol, bevantolol, bukmorol, bufetolol, bupralol, bunitrolol, bupranolol, bubutolol Topyrrole, Carrazorol, Capterool, Carvedilol, Celiprolol, Cetamolol, Direvalol, Epanolol, Esmolol, Indenolol, Labetalol, Mepindorol, Metipranolol, Metoprolol, Morphrolol, nadorol, nadoxoroll, nebivorol, nifenarol, nifridarol, oxprenolol, fenbutolol, pindorol, practorol, pronetrol, propranolol, sotarol, sul Pinarol, tallolinol, tetatorol, tilisorol, timolol, toliprolol, xibenolol;
    Antithrombotic drugs and vasodilators: Acetpan, acetylsalicylic acid, argatroban, methane, benprodil, hemisuccinic acid, beziodarone, betahistin, brovincarmine, bufeniod, citcholine, chlorine Benprol, Clopidogrel, Cyclendelic Acid, Dalteparin, Dipyridamol, Droprenylamine, Enoxaparin, Pendylin, Ifenprodil, Iloprost, Indobufen, Isvogrerel, Isosuphrine, Heparin, Ramipivan , Mididorin, nadroparin, nicotinyl alcohol, niliderin, ozagrel, perhexylline, phenylpropanolamine, prenylamine, papavenoline, sodium levparin chloride, lidogrel, sulfoctidyl, tinophedrine , Tinzaparin, triflusal, xanthinolinic acid;
    Diabetic agents: acarbose, carbutamide, glyborgnuglybutiazoyl, miglitol, repaglinide, troglitazone, 1-butyl-3-methanyl-uea, tolesatt, nicotinamide;
    Antitumor drugs: Ancitabine, Anthramycin, Azacytidine, Azaserine, 6-Azauridine, Bicalutamide, Carrubicin, Carboxinophylline, Chlorambucil, Chlorozotocin, Cytarabine, Daunorubicin, Dephosphopamide, demecolsin, denophtherine, 6-diazo-oxo-L-norleucine, docetaxel, doxyfluidine, doxorubicin, droloxifene, etatrexane, eplonitine, enositabine, epi Rubicin, epithiostanol, etanidajoil, etoposide, penretinide, fludarabine, fluorouracil, gemcitabine, hexestrol, idarubicin, ronidamin, mannomustine, melphalan, meno Garyl, 6-mercaptopurine, methotrexane, mitobronitol, mitolactol, mitomycin, mitoxantrone, furdamol, mycophenolic acid, ninophtherine, nogalamycin, paclitaxel, pentostatin, pyrarubicin Sin, pyritrexim, plicamycin, grape phytic acid, sodium former, porphy Mycin, propagermanium, puromycin, lanimuscitin, retinoic acid, loquinimex, streptonigrin, streptozosin, teniposide, tenuazoic acid, thiamiprine, thioguanine, tomusdex, topotecan , Trimetrex acid, tubercidine, ubenimex, vinblastine, vincristine, vindesine, vinorelbine, zorubicin;
    Anti-ulcer drugs: ε-acetamide caproic acid, arbaprostill, setaxic acid, cimetidine, ecabet, enprosteel, esaprazoil, irsogladine, misoprostol, omeprazoil, ornoprostill , Pantophrazoyl, flaunotol, lioprostil, rosaprostol, lordaxic acid, sofalcone, trimoprostill;
    Antihyperlipidemic drugs: atorvastatin, cilastatin, termostatin, flvastatin, lovastatin, mevastatin, nystatin, pentostatin, pepstatin, sodium prevastatin, simvastatin;
    Antibiotics: Amdinocillin, Amoxicillin, Ampicillin, Apalcillin, Apicycline, Aspoxicillin, Azidamphenicol, Azidocillin, Azrocillin, Aztreonam, Benzoylpas, Benzylpenicillin, Viapenem, Bikozamycin, Capreomycin, Carbenicillin, Carindacillin, Kalumonam, Sephacror, Sephadroxil, Sephamandol, Sephatrizin, Sephazedon, Sephazolin, Sepbuferrazone, Cephclidine, Cef Dinir, ceftitorene, cefepime, cefetameth, seppicsim, pefmenoxime, ceftamezoyl, cefminox, cedidimide, cenisid, cefeperazone, celanide, cefotaxime, cetetan, ceftiam , Cytoxitine, cytozofran, cefepimizole, ceftyramide, ceftirom, ceftrozil, ceproxadine, ceftsulodine, ceftazidime, cefteram, ceftezoyl, ceftibuten, ceftiofur , Safety class, ceftriaxone, cepuroxime, cepuzo , Cephacetyl sodium, cephalexin, cephaloclycin, cephaloridine, cephalosporin C, cephalotin, cephapyrine sodium, cepradine, chloramphenicol, chlortetracycline, synoxacin, clavulanic acid , Clometocillin, Clooxacillin, Cyclacillin, Cycloserine, Demeclocycline, Diclooxacillin, Epicillin, Penvecillin, Flomoxef, Flooxacillin, Hetacillin, Imiphenem, Nenampicillin, Laura Capvef, Rimesiclin, Mafenide, Meclocycline, Meropenem, Metaampicillin, Metacycline, Sodium Methicillin, Mezlocillin, Minosicline, Moxalactam, Mupyrosine, Mycin, Nexamycin , Novobiocin, Oxacillin, Panichenem, Potassium Chloride Penicillin G, Penicillin N, Penicillin O, Penicillin V, Potassium Chloride Penicillin, Pipacycline, Piperacillin, Pyrimycin, Porphyromycin, Propicillin, Quinacillin , Riptpenem, lolitetracillin, shaanxi Clin, cedemycin, spectinomycin, sulfactam, sulfenicillin, temocillin, tetraxillin, tacarcillin, tigemonam, tubercidine, azithromycin, clarithromycin, dirithromycin, Enbiomycin, erythromycin, probemycin, middecamycin, myokamycin, oleandomycin, rifabutin, lipamide, rifamycin, lipamycin, locamycin, spiramycin, troleandromycin, biomycin, Virginiamycin; Amikacin, apramycin, arbecasin, dibecasin, dihydrostreptomycin, fortimycin, gentamicin, micronomycin, neomycin, netylmycin, paromomycin, ribostamycin, sisomicin, spec Tinomycin, streptomycin, tobramycin, tropectomycin; Bacampicillin, Cochsylcepchafen, Proxetylcepofoxime, Pannimem, Pibampicillin, Fibcephalexin, Sulamicillin, Talampicillin; Carbomycin, Clindamycin, Lincomycin, Micamycin, Rosaramimycin, Ciprofloxacin, Crinafloxacin, Difloxacin, Enoxacin, Enlofloscin, Floxacin, Flumequine, Glepafloxacin, Lomefloxacin , Nadifloxacin, nalidic acid, norfloxacin, oploxacin, pajufloxacin, pefloxacin, pipemide, pyromidic acid, lufloxacin, sparfloxacin, tosufloxacin, trobafloxacin , Chlomocycline, Guamecycline, Oxytetracycline, Nipurininol, Nipurrazine; p-aminosalicylic acid, p-aminosalicylic acid hydrazide, clofazimin, deoxydihydrostreptomycin, ethambutol, glyconiazide, isoniazid, opiniazide, phenylaminosalicylic acid, rifampin, pipefatin, salinazide, 4-4 ′ Sulfinyldianiline, acediasulfone, dapsone, succisulfone, p-sulfanilibenzylamine, thiazoylsulfone, acetylsulfamethoxypyrazine, maphenide, 4 '-(methylsulfamoyl) sulfanylanilide, sala Zosulfadimidine, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, Sulfaclisoidine, Sulfachitin, Sulfadiazine, Sulfadicuramide, Sulfadimethine, Sulfadoxin, Sulfathidol, Sulfaguanidine, Sulfagua Knol, Sulfalen, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfametijoil, Sulfametomidine, Sulfametoxajo, Sulfamethoxypyridazine, Sulfamethylthiazole, Sulfametrol, Sulfamidorizo Dean, Sulfur , Sulfanyl amide, 2-p- sulfanyl GW carbonyl Reno ethanol, N 4 - sulfanyl rilsul isoquinoline amides, isoquinoline rilru Lea, N- sulfanyl-3,4 keusil vanillyl amide, sulfamic Perrin, Pape alcohol or one trillion days, Sulfaprooxylin, sulfapyrazine, sulfapyridine, sulfasomizoyl, sulfazimazin, sulfatiazoyl, sulfatiurea, sulfisomidine, sulfisoxazoyl, 4-sulfanamidosalicylic acid; Negamycin, Carmonan, Clooxyquine, Nitrooxolin, Arginine, Metronidazole;
    Antiviral drugs: acyclovir, amantadine, sipofovir, cytarabine, didanosine, dideoxyadenosine, edoxsudine, famcyclovir, phloxuridine, gancyclovir, idoxuridine, indanavir, ke Toxal, lamivudine, MADU, pennylclovir, grapephylotoxin, ribavirin, rimantadine, saquinavir, sorivudine, stavudine, trifluridine, valacyclovir, vidarabine, xenazoic acid, zalcitabine, zidobudine;
    Aggregate absorption inhibitors: alendronic acid, butedronic acid, etidronic acid, oxide acid, pamideronic acid, risedronic acid;
    Antidementants: Compounds selected from amiridine, razabemid, mopegiline, salvelozoil, oxyracetam, ipidacrine, nebracetam, tacrine, belnakrine.
    [11" claim-type="Currently amended] The method of claim 9 or 10, wherein the precursor drugs are
    Anti-inflammatory agents: acetylsalicylic acid, 5-aminoacetylsalicylic acid, carpropene, diclofenac sodium, diflunisal, etodorak, flufenamic acid, flunicin, flurbiprofen, ibuprofen, indomethacin, indopropene, keto Propene, Ketorolac, Rolloxycam, Roxopropene, Meclofenamic Acid, Mefenamic Acid, Meloxycam, Mesalamine, Naproxen, Niplum Acid, Olsarazine, Pyrocamcam, Salsalic Acid, Surindak, Water Propene, tenoxycam, thiapropenic acid, tolfenamic acid, tolmetin, zomepilac, civil ciprolol;
    Analgesics: acetaminophen, acetylsalicylicsalicylic acid, benoxapropene, buprenorphine, butorpanol, capsacin, diaserine, dihydrocodeine, ethylmorphine, eugenol, phenylbutazone, meptazinol, Morphine, nalbuphine, phenazosin, thiorphan, tramatol, acrotite;
    Drugs and bronchodilators acting on the cholinergic system: albuterol, carbuterol, clenbuterol, diphylline, etophylline, phenoterol, bromide pratropium, metaproterenol, oxybutynin, pybuterol, Salmeterol, terbutalin, thiopromium bromide, japriast, cyclodrin, NS-21, 2-hydroxy-2,2-diphenyl-N- (1,2,3,6-tetrahydro- Pyridin-4-ylmethyl) acetamide;
    Expectorant / mucolytic drugs: ambroxol, brominehexine, guaiacol, sobreol;
    Anti-asthmatic / antiallergic antihistamines: cetirizine, histamine, levocarbastine, rodoxamide, montelukast, terpenadine, bromine hexine;
    ACE inhibitors: captopril, enalapril, ricinopril, nosartan, ramipril;
    Beta-blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindorol, propranolol, timolol;
    Antithrombotic drugs and vasodilators: acetylsalicylic acid, acetoban, argatroban, clopidogrel, dalteparin, dipyridalmol, enoxaparin, heparin, iloprost, midoderin, ozagrerel, phenylpropanolamine , Triflusal;
    Diabetes mellitus: torestat, nicotinamide;
    Anti-tumor drugs: anthracycin, daunorubicin, doxorubicin, epirubicin, fluorouracil, methotrexane, vinblastine;
    Anti-ulcer drugs: cimetidine, omeprazoil, pantophrazoil;
    Antihyperlipidemic drugs: lovastatin, pravastatin sodium, simvastatin;
    Antibiotics: Amoxicillin, Ampicillin, Aztreonam, Viapenem, Carbenicillin, Sephacror, Sephadroxil, Sephamandol, Sephatrizin, Selcytin, Clavulanic Acid, Diclooxacillin, Imipenem, Meclo Cyclin, metacycline, moksalactam, panipenem, sulbactam, azithromycin, erythromycin, probemycin, myokamycin, rifabutin, lipamide, rifamycin, gentamicin, paromomycin, sisomycin , Bacampicillin, Carbomycin, Clindamycin, Ciprofloxacin, Crinafloxacin, Difloxacin, Enlofloscin, Lomefloxacin, Nadifloxacin, Norfloxacin, Pipemedic acid, Apicycline, Chlomocycline , Oxytetracycline, nifurpynol, nipurrazine, isoniazid, rifampin, pipepafentin, dapson, thiazosulfone, sulfametoxazoyl, sulfamoxol, metronidazoil, arginine;
    Antiviral drugs: acyclovir, famcyclovir, gancyclovir, pencilclovir, ribavirin, vidarabine, zidovudine;
    Aggregate Absorption Inhibitors: Compounds selected from alendronic acid, etidronic acid, and pamidronic acid.
    [12" claim-type="Currently amended] The method according to any one of claims 1 to 8, wherein the precursor drugs are A = R- steroid compounds,

    Wherein in the substitution of hydrogens of the CH groups or of two hydrogens of the CH 2 groups mentioned in the general formula, the following substituents may be represented:
    Position 1-2: may be a double bond;
    Position 2-3: may be a substituent below;

    2-position: may be Cl, Br;
    3-position: CO, —O—CH 2 —CH 2 —Cl, OH;
    3-4 position: may be a double bond;
    4-5 position: may be a double bond;
    Position 5-6: may be a double bond;
    Position 5-10: may be a double bond;
    6-position: may be Cl, F, CH 3 , -CHO;
    7-position: may be Cl, OH;
    9 position: may be Cl, F;
    11-position: may be OH, CO, Cl, CH 3 ;
    16 position: CH 3 , OH, = CH 2 ;
    17-position: OH, CH 3 , OCO (O) ua (CH 2 ) va CH 3 , or

    May be (ua is an integer from 0 or 1 and va is an integer from 0 to 4);
    Positions 16-17 may be the following groups:

    R and R ', which are the same or different from each other, may be hydrogen or linear or branched alkyls of 1 to 4 carbon atoms, preferably R = R' = CH 3 ;
    R "is Where t2 = 1 when t = 0, t2 = 0 when t = 1, and t and t1, or t2 and t1, when A does not contain -OH groups, can be 0 simultaneously With no conditions, t, t1 and t2 are integers equal to or different from each other, 0 or 1;
    The bivalent bite group (L) And na, n'a, and n''a, which are the same or different from each other, are integers from 0 to 6, preferably 1 to 3, and nb, n'b, n''b and the same or different from each other; n '' ′ b are integers equal to 0 or 1, and the same or different R 4 , R 5 are selected from hydrogen, linear or branched alkyl of 1 to 5, preferably 1 to 3 carbon atoms;
    Is X as defined above, Same as where Is OH, CH 3 , Cl, N (-CH 2 -CH 3 ) 2 , SCH 2 F, SH, or

    Phosphorus compounds.
    [13" claim-type="Currently amended] The compounds of claim 12, wherein R ″ = — CO—CH 2 OH, —CH (CH 3 ) —CH 2 —CH 2 —COOH.
    [14" claim-type="Currently amended] 14. Compounds according to claim 12 or 13, wherein the precursor steroids are selected from precursor steroids having a hydroxyl group at position 3 and / or position 11 and / or having a hydroxyl group or carboxyl group at the terminal position of R ″.
    [15" claim-type="Currently amended] 15. The method of any of claims 12-14, wherein the precursor steroids are
    Budesonide, hydrocortisone, alclomethasone, alzestone, beclomethasone, betamethasone, chloroprednisone, clobetazoil, clobetason, clocotorone, clopredol, cortisone, corticosterone, diplazacoat , Desonide, desomimethasone, desamemethasone, diflorasone diflucotorone, difluprenate, fluazacoat, fluchloronide, flumethasone, flunisolide, fluorinolone acetonide, fluorino Nide, Fluorocortin Butyl, Fluorocortone, Fluoromethorone, Fluferonone Acetate, Flupredenide Acetate, Fluprednisolone, Flulandrenolide, Formomotal, Halcinolone, Halobetasol Propionate, Halo Metason, halopredone acetate, hydrocomate, loteprednol etabonate, meridone, meprednisone, methylprednisolone, mometasone puro Nitrate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednisbal, prednylidene, limexolone, triamcinolone, triamcinolone Acetonide, 21-acetocypregnenolone, cortivazoil, amcinonide, fluticasone propionate, marzipredone, tisocortol, triamcinolone hexaacetonide, ursodesuccinic acid, chenodesuccinic acid, Compounds selected from mitatrienediol, mozzestrol, ethynylestradiol, estradiol, mestranol.
    [16" claim-type="Currently amended] Use of a compound or salt according to any one of claims 1 to 15, or a combination thereof, used in medicine.
    [17" claim-type="Currently amended] Use of a compound or salt according to any one of claims 1 to 15, or a combination thereof, for the preparation of oxidative stress treatment drugs.
    [18" claim-type="Currently amended] A pharmaceutical formulation comprising the compound or salt of any one of claims 1 to 15 as an active ingredient.
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    同族专利:
    公开号 | 公开日
    WO2000061549A3|2002-01-03|
    BR0009701A|2002-04-02|
    NO20014926D0|2001-10-10|
    HU0200747A3|2003-02-28|
    MXPA01010209A|2003-07-21|
    CA2370406A1|2000-10-19|
    JP2002541242A|2002-12-03|
    TR200102939T2|2002-09-23|
    ITMI990750A1|2000-10-13|
    IL145632D0|2002-06-30|
    EP1192129A2|2002-04-03|
    IT1311921B1|2002-03-20|
    CN1356981A|2002-07-03|
    AU3820000A|2000-11-14|
    HU0200747A2|2002-06-29|
    WO2000061549A2|2000-10-19|
    NO20014926L|2001-12-13|
    PL351241A1|2003-04-07|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-04-13|Priority to ITMI99A000750
    1999-04-13|Priority to IT1999MI000750A
    2000-04-11|Application filed by 니콕스 에스. 에이.
    2000-04-11|Priority to PCT/EP2000/003237
    2002-01-17|Publication of KR20020005671A
    优先权:
    申请号 | 申请日 | 专利标题
    ITMI99A000750|1999-04-13|
    IT1999MI000750A|IT1311921B1|1999-04-13|1999-04-13|pharmaceutical compounds.|
    PCT/EP2000/003237|WO2000061549A2|1999-04-13|2000-04-11|Pharmaceutical compounds|
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